Leukemia (2008) 22, 915–931; doi:10.1038/leu.2008.19; published online 21 February 2008

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

A Renneville1,4, C Roumier1,4, V Biggio1, O Nibourel1, N Boissel2, P Fenaux3 and C Preudhomme1

  1. 1Laboratoire d'Hématologie A, INSERM U837-Institut de Recherche sur le Cancer, CHU of Lille, North-West Canceropole, France
  2. 2Service d'Hématologie Adulte, Hôpital Saint-Louis, Paris, France
  3. 3Service d'Hématologie Clinique, Hôpital Avicenne, Bobigny, France

Correspondence: Professor C Preudhomme, Unité INSERM 837 and Laboratoire d'Hématologie A, Centre de Biologie-Pathologie, CHU of Lille, Boulevard du Pr Leclercq, Nord, Lille 59037, France. E-mail:

4These authors contributed equally to this work.

Received 25 May 2007; Revised 5 January 2008; Accepted 18 January 2008; Published online 21 February 2008.



Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.


acute myeloid leukaemia, mutations, proliferation, differentiation, prognosis, review



Acute myeloid leukemia (AML) is a phenotypically and genetically heterogeneous but aggressive disease. Major progress has been made to understand mechanisms of leukemogenesis in AML. One of the most relevant hypothesis is the implication of a primitive hematopoietic stem cell or progenitor cell capable of transformation in a so-called leukemic stem cell (LSC), which keeps the ability to self-renewal. This LSC comes from the accumulation of genomic alterations affecting proliferation, cell death and the perturbation of genes involved in the carefully regulated pathways of hematopoietic differentiation. These key oncogenic events are often divided into two classes according to the two-hit model hypothesis of leukemogenesis, in which class I mutations (such as FLT3-ITD) confer a proliferation or survival advantage to blast cells, while class II mutations block myeloid differentiation and give self-renewability.1 Such events have now been observed in different types of AML. Differentiation blocks can occur by alteration at specific stages, like mutations of CEBPA gene or of the core-binding factor (CBF) complex genes, including RUNX1, which results in different subtypes of AML.

The two-hit model of leukemogenesis, combining an activating lesion of tyrosine kinase pathways with an event blocking myeloid differentiation, appears very interesting not only to modelize in vitro leukemogenesis, but also to screen molecular events in AML patients, as observed by the frequent association of an FLT3-ITD mutation with a fusion transcript like AML1-ETO or PML-RARA.1 Over the past years, besides deregulation of myeloid differentiation resulting from the expression of chimeric proteins, numerous gene mutations have been reported in different types of AML.

In this article, we reviewed, in AML, mutations of genes that contribute to cell proliferation by alteration of tyrosine kinase signaling (FLT3, c-KIT, RAS...) or tyrosine phosphatase (PTPN11) pathways, mutations of genes involved in myeloid differentiation (AML1, CEBPA) and in the regulation of cell cycle and apoptosis (NPM1, P53).


Gene mutations inducing a proliferative advantage


The FMS-like tyrosine kinase 3 (FLT3) gene, located on chromosome 13q12, encodes a membrane-bound receptor tyrosine kinase (RTK) that belongs to the RTK subclass III family, characterized by five immunoglobulin-like extracellular domains, a single transmembrane domain, a juxtamembrane domain (JMD) and an intracellular domain consisting of two protein tyrosine kinase (PTK) domains linked by a kinase-insert domain. Other members of the RTK subclass III include macrophage colony-stimulating factor (M-CSF) receptor, c-KIT and the receptors for platelet-derived growth factors A and B (PDGFRA and PDGFRB).2 FLT3 is normally expressed by myeloid and lymphoid progenitor cells and expression is lost as hematopoietic cells differentiate. FLT3 plays an important role in the proliferation, differentiation and survival of multipotent stem cells3 and is overexpressed at the RNA and protein level in AML blasts.4 FLT3 is one of the most frequent somatic alterations in AML, found in 25–45% of all AML patients. FLT3 mutations consist of two major types. The most common type is an intern tandem duplication (ITD) in exons 14 and 15 (previously known as exons 11 and 12) that map to the JMD, seen in 25–35% of adult and 12% of childhood AML.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 These ITD, and deletion or insertion/deletion mutations affecting the JMD, are sometimes called length mutations (LM) in the literature. Here, we use the term ITD to refer to all JMD mutations.13, 14, 15, 16 The length of the duplicated JMD region varies from 3 to 400 nucleotides but, despite this heterogeneity, the resultant transcripts are always in-frame.17 The second most common type of FLT3 mutation is a missense point mutation in exon 20, within the activation loop (AL) of the tyrosine kinase domain (TKD), found in 5–10% of AML patients. This mutation typically involves codons D835 and/or I836, and less frequently N841 or Y842.18 Several point mutations in the JMD have also recently been described in some AML cases. Their prevalence seems to be lower than 1% in all AML subtypes and has not yet been established in cytogenetically normal AML (CN-AML).19, 20 Lastly, a novel gain-of-function mutation (K663Q), located not in the AL but in the N-terminal part of TKD, has been recently identified in AML.21 Interestingly, a recent study stressed the importance of functional studies, since among the different FLT3 mutations reported outside the JMD and the TKD, some were not associated with kinase activation, and did not contribute to leukemogenesis.22 Most affected AML patients have only one type of FLT3 mutation, but some patients have both an ITD and TKD of FLT3.

FLT3 mutations lead to constitutive phosphorylation of the receptor in the absence of FLT3 ligand and consecutive activation of the downstream signaling pathways such as phosphatidylinositol 3 kinase/AKT, Ras/mitogen-activated protein kinase (MAPK) and Janus kinase 2 (JAK2)/STAT5.20, 23, 24 However, there is increasing evidence suggesting that the downstream cellular responses to FLT3-ITD and FLT3-TKD mutation are not equivalent. In murine bone marrow transplantation models as well as in transgenic mice, FLT3-ITD induces a myeloproliferative disease that closely resembles human chronic myelomonocytic leukemia, and FLT3-TKD an oligoclonal lymphoid disorder with longest latency, but neither FLT3-ITD nor FLT3-TDK mutations induce AML.23, 24, 25 These findings support the idea that FLT3 alterations are not sufficient to cause AML. Furthermore, the fact that FLT3 mutations can be acquired or lost at relapse or during disease progression is in accordance with the hypothesis that FLT3 mutations are secondary events in leukemogenesis.3, 26

The frequency of FLT3-ITD mutations varies dramatically across cytogenetically and molecularly defined subsets of AML. FLT3-ITD has a particularly high incidence in CN-AML and t(15;17)-positive AML (30–35% of cases in each group), and in AML with t(6;9).7, 27, 28, 29 FLT3-ITD-positive patients are more often diagnosed with de novo than secondary AML.7, 8 Both FLT3-ITD and -TKD mutations have been strongly associated with high white blood cell (WBC) count and high bone marrow blast percentages at presentation.5, 7, 9, 10, 30 A positive correlation between MLL (mixed lineage leukemia) intragenic abnormalities (MLL partial tandem duplication (MLL-PTD) or DNA double-strand breakage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors) and FLT3 mutations (ITD and TKD) has been reported.31 In contrast, there is an almost mutually exclusive occurrence of FLT3 and RAS mutations in AML samples.32, 33

Many studies have shown that FLT3-ITD has a negative impact on outcome in both adult and pediatric AML patients. FLT3-ITD confers a poor prognosis due to an increased relapse rate, reduced disease-free survival (DFS) and overall survival (OS), while the rate of complete remission (CR) is not significantly affected.34 Several studies restricted to CN-AML have demonstrated that patients harboring at least one allele with FLT3-ITD had a significantly shorter CR duration (CRD), and OS than patients without FLT3-ITD. Moreover, FLT3-ITD has been found to be an independent prognostic factor for OS, and CRD in CN-AML.5, 7, 35 However, in other cytogenetic subsets including t(15;17) AML, FLT3-ITD appears not to be an independent prognostic factor.36, 37

The molecular characteristics of FLT3-ITD are extremely variable among patients. FLT3-ITDs are found in the heterozygous state, but they are sometimes found in a homozygous state after loss of the normal FLT3 allele. A particularly bad prognostic subgroup consists of patients who have lost the wild-type (WT) allele of FLT3.5 Among intermediate-risk AML, patients with low allelic ratio quantified by Genescan analysis (mutated/WT FLT3<0.8) appear to have survival comparable to AML patients without FLT3-ITD mutations. The absence of FLT3 WT allele likely results from acquired uniparental disomy, which could be either partial, due to somatic recombination between homologous chromosomes occurring after FLT3-ITD had been generated, or could involve loss of the entire chromosome 13 with the WT allele and subsequent duplication of the remaining homologous chromosome 13 with FLT3-ITD.38, 39 Another explanation to the variation of allelic ratios lies in the fact that FLT3-ITD may occur only in a subclone of malignant cells and not in LSC. Differences in the size of the duplicated insert may also explain some of the prognostic variability of FLT3-ITDs. A recent study found that patients with larger duplicated segment (over 40 nucleotides) had worse DFS and OS than patients with smaller ITDs.40 However, this finding was not confirmed by others41, 42 and needs to be tested on larger cohorts of patients.

In contrast to FLT3-ITD, the prognostic impact of TKD point mutations of FLT3 is still controversial.7, 30, 34, 43 According to a recent study, the impact of FLT3-TKD mutations on OS when including all mutant-positive patients was not significant, but patients with high-level mutations (more than 25% mutant) had significantly improved outcome.30 Further studies are however necessary to determine the clinical relevance of FLT3-TKD, especially in relation with other molecular prognostic factors.

FLT3 mutational status may change between diagnosis and relapse, with about 9% (4–27% ) of patients losing their FLT3-ITD mutation at relapse, whereas approximately 6% acquire FLT3-ITD mutation on this occasion. Moreover, in about 6% of FLT3-ITD-positive patients, the length or number of FLT3-ITD change at relapse.26, 44, 45, 46 The situation is very different for FLT3-TDK mutations, which are lost at relapse in more than 50% of cases.47 This again strongly suggests that FLT3 alterations are secondary genetic events, occurring in a subclone and not in the LSC. In addition to be a prognostic marker, FLT3-ITD is a potential target for minimal residual disease (MRD) monitoring and for the development of novel treatments. However, the use of FLT3-ITD as MRD marker is limited by its relative instability during follow-up, as discussed later in this review.


The Kit proto-oncogene, located on chromosome band 4q12, encodes a transmembrane glycoprotein, which is a member of the type III RTK family, and whose ligand is stem cell factor (SCF).48, 49 SCF binding promotes c-KIT dimerization and transphosphorylation that leads to activation of downstream signaling pathways involved in proliferation, differentiation, migration and survival, particularly of hematopoietic stem cells. Ligand-independent activation of c-KIT can be caused by different types of mutations that have been reported in AML and also in other human malignancies (including mast cell disorders, gastrointestinal stromal tumors, and testicular germ cell tumors).50 Gain-of-function mutations may affect either the extracellular portion of c-KIT receptor, believed to play a role in the dimerization (in-frame insertion/deletions of exon 8 that all result in loss of the acid aspartic residue at amino acid 419), or the JMD (ITD of exon 11), or the structure of the AL in the TKD, such as the substitution of a single amino acid in exon 17 (mostly mutation D816V, and less commonly other mutations affecting codon 816 (D816Y/H/F/I), 821, 822 or 823).51, 52, 53, 54 Codon 816 c-KIT mutations were shown to induce constitutive activation of PI3K and downstream of PI3K, Jnk1 and Jnk2, as well as STAT3 and upregulation of STAT3 downstream targets, such as BLCXL and MYC.55, 56 c-KIT mutations have been identified with a particularly high incidence in specific cytogenetic subsets of AML: CBF AML and AML with trisomy 4 (as either the sole cytogenetic aberration or associated with t(8;21)), and are generally not observed in other AML subtypes, such as AML with t(15;17) or with complex karyotype. Likewise, c-KIT mutations are not equally distributed among FAB subtypes and are mainly found in M1, M4, M4eo and particularly in M2, since nearly 70% of c-KIT-mutated AML patients are classified as M2.51, 52, 53, 57, 58, 59 The overall frequency of c-KIT D816 and exon 8 mutations in AML is approximately 2% (33/1940)58 and 6–8% ,51, 52, 53, 54, 55, 56, 57, 58, 59 respectively. In contrast, c-KIT D816 and exon 8 mutations have been reported with an average incidence of 16 and 12% among AML patients with t(8;21), and 13 and 22% among AML patients with inv(16), respectively.51, 52, 53, 57, 58, 59, 60, 61, 62, 63 Recently, a complex c-KIT ITD involving exon 11 and exon 12 was identified in 4/60 (7% ) of childhood AML.64 The incidence of c-KIT D816 mutations was found not to significantly differ between de novo AML, AML secondary to myelodysplactic syndromes (MDS) and therapy-related AML (t-AML).58 In AML with t(8;21), the presence of c-KIT mutations is associated with a higher WBC count at diagnosis.60, 61 Some authors described a negative association between c-KIT and FLT3 mutations, but both alterations are not mutually exclusive.58, 60 Functional redundancy is a potential reason for the fact that mutations of these two RTK are rarely found to co-exist in the same patient. This supports the findings that activating mutations of c-KIT and FLT3 are associated with distinct cytogenetic AML subgroups, respectively CBF AML and AML with normal karyotype and t(15;17).53, 58, 59, 60, 62 In CBF AML, c-KIT D816 and exon 8 mutations appear to predict a higher incidence of relapse.52, 58, 60, 61, 62, 63 In some studies, c-KIT exon 17 mutations were also significantly associated with shorter CRD and OS in adult and pediatric AML with t(8;21).58, 60, 61, 62, 63 According to Paschka et al.,63 both exon 17 and exon 8 mutations appear to adversely affect OS in AML with inv(16). Overall, these data indicate that c-KIT mutations have a significant negative impact on the outcome of CBF AML, especially D816 mutation in AML with t(8;21). Detection of c-KIT mutations in CBF AML is important not only for outcome prediction, but also for therapeutic implications since c-KIT-activating mutations may represent a target for tyrosine kinase inhibitors (TKI).


RAS oncogenes encode a family of guanine nucleotide-binding proteins that regulate signal transduction on binding to a variety of membrane receptors, including c-KIT and FLT3, and play an important role in proliferation, differentiation and apoptosis processes. RAS proteins normally exist in an equilibrium between active (GTP-bound) and inactive (GDP-bound) states.65, 66 There are three functional RAS genes: N-(from a neuroblastoma cell line), K-(Kirsten) and H-(Harvey) RAS, each containing four exons. Mutations in N- or K-RAS occur nearly exclusively by one base change in codons 12, 13 or 61, which abrogate intrinsic RAS GTPase activity and thus confer constitutive activation of RAS proteins and downstream effectors, such as RAF and MAPK/ERK kinases.67

Point mutations in N- and K-RAS genes are found in approximately 10–15 and 5% of all AML patients, respectively. Codons most frequently mutated are N-RAS codon 12 (43% ), mostly resulting in changes from glycine to asparagine, N-RAS codon 13 (21% ) and K-RAS codon 12 (21% ).68, 69 All of the mutated patients were found heterozygous for the mutation. In MDS studies, RAS mutations have been found to be significantly associated to progression from MDS to AML.70, 71 In AML, RAS mutations frequency does not seem to vary significantly with age, sex, initial leukocytosis, WHO (World Health Organization) performance status and de novo versus secondary or t-AML.68, 69, 72, 73 The subgroup of AML with inv(16)/t(16;16) and inv(3)/t(3;3) shows a significantly higher frequency of RAS mutations than in other groups, approximately 35 and 27% , respectively, with N-RAS codon 61 being significantly more frequently involved than in other patients.59, 60, 68, 69 By contrast, RAS mutations are significantly less common in AML with t(15;17) (2% ) and with complex aberrant karyotypes (1.5% ). RAS mutations are relatively overrepresented in FAB type M4eo/inv(16),68, 69 and, in some studies, in M4 AML.59, 74 RAS mutations and FLT3-ITD were found to co-exist in only 16 of 815 (2% ) patients analyzed for the two mutations, indicating a significant negative association between them.32, 68 The rarity of RAS mutations in FLT3 mutants, and vice versa, is in line with the two-hit model of AML pathogenesis. Contrary to MDS studies,70, 71 most large studies found no significant prognostic impact of RAS mutations for OS, CR rate and CRD in AML.32, 59, 60, 68, 69, 73, 74, 75 In 107 patients for which N-RAS mutations status was studied both at diagnosis and at relapse, findings were similar in 102/107 (95% ) patients at diagnosis and at relapse. However, one patient gained a mutation at relapse whereas four out of eight RAS-mutated patients had no more mutation at relapse, indicating that N-RAS mutations are not good markers for follow-up control of residual disease after treatment69 and arguing against a role for RAS mutations as primary leukemogenic events.


The PTPN11 gene (protein tyrosine standard phosphatase nonreceptor 11), located on chromosome 12q24, encodes a cytoplasmic protein tyrosine phosphatase (PTP) called SHP-2. The SHP-2 protein has three functional domains: two tandem SH2 (Src homology 2) domains at the N-terminal (N-SH2 and C-SH2) that both positively regulate SHP-2 activity and a single catalytic (PTP) domain at the C terminus. The N-SH2 domain basically interacts with the PTP domain and blocks the catalytic site. After binding the phosphotyrosyl substrate, the N-SH2 domain undergoes a conformational change that weakens the autoinhibiting intramolecular interaction, making the catalytic site available to substrate, thereby activating the phosphatase. The substrates upon which SHP-2 acts are not known with certainty.

SHP-2 participates in signal transduction downstream of growth factor, cytokines, hormones and cell adhesion molecules. SHP-2 is highly expressed in hematopoietic cells and is implicated in the response to KIT-ligand, interleukin-3 (IL-3), IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and EPO. The regulatory function of SHP-2 is complex, but, in most circumstances, it plays a positive role in transducing signals, which is mediated, at least in part, through the Ras/MAP kinase cascade.76

Germ-line mutations in PTPN11 are seen in more than 50% of cases of Noonan's syndrome, an autosomal dominant disorder characterized by facial dysmorphy, skeletal malformations and a wide spectrum of heart defects.77 Somatic mutations in PTPN11 are found in about 35% of juvenile myelomonocytic leukemia (JMML) cases. JMML patients without PTPN11 mutations have either RAS mutations or homozygous neurofibromatosis-type 1 gene deletion or inactivation, illustrating the important role of activated RAS in this disease.76 With the exception of two trinucleotide deletions described in patients with Noonan syndrome, all the PTPN11 mutations reported so far have been missense substitutions that result in gain-of-function of SHP-2 catalytic activity. The vast majority of mutations cluster in the interacting portions of the N-SH2 domain and the PTP domains involved in switching the protein between its inactive and active conformations. Like in other myeloid malignancies, >80% of the mutations identified in AML are localized in exon 3, with lesions altering codons 72 and 76 accounting together for nearly 50% of all mutations reported in AML.76 The role of SHP-2 in AML pathogenesis remains to be fully determined. However, genetic evidence supports the hypothesis that PTPN11 mutations contribute to leukemia growth by deregulating the RAS pathway. The existing data do not permit to determine if somatic SHP-2 mutations can initiate AML or represent a secondary event, acquired during disease evolution.78

Approximately 4.4% (31/702) of pediatric AML cases show PTPN11 mutations.79, 80, 81 The prevalence of PTPN11 mutations among adult AML patients seems to be lower since only 9 (2.6% ) mutations were observed in nearly 340 adult patients with secondary or de novo AML.76, 82, 83, 84 In pediatric AML, the probability of achieving CR, CRD and OS was found similar in patients with and without PTPN11 mutations, but the power to detect significant differences was diminished by the low frequency of mutations.79, 81 The prognostic impact of PTPN11 mutations in adult AML has not been evaluated. One report found that PTPN11 mutations occurred preferentially in AML with FAB M5 morphology (12 versus 1.5% in non-FAB M5),76 but this finding was not confirmed by Goemans et al.80 Within the FAB-M5 group, no significant association with any clinical variable was found. Similarly, the presence of PTPN11 mutations was not related to any specific-gene rearrangement or cytogenetic risk group.79 In 7/32 (22% ) pediatric AML patients with PTPN11 mutations, RAS and/or FLT3 lesions were found to co-exist.79, 80, 81

Other mutated genes

JAK2 is a cytoplasmic tyrosine kinase involved in signaling pathways by members of the single chain receptors (for example, EPOR, TPOR), the IL-3 receptor family (IL-3R, IL-5R and GM-CSF-R), the Gp130 receptor family and the class II receptor cytokine family. JAK2 plays a key role in signal transduction initiated by multiple growth factor-receptors and cytokines required in hematopoiesis.85, 86 The recurrent JAK2V617F mutation causes replacement of a key valine residue by phenylalanine in the pseudo-kinase domain JH2 that has an inhibitory role on the kinase domain JH1. The mutant enzyme had enhanced kinase activity and leads to hyperactivation in downstream signaling components, STAT5, PI3K/Akt, ERKs. JAK2V617F mutation is present in more than 90% of polycythemia vera (PV) cases, in approximately 50% of essential thrombocythemia (ET) and myelofibrosis with myeloid metaplasia (MMM) cases and in about 70% of patients with AML following myeloproliferative disorders. By contrast, JAK2V617F mutation is a rare event in de novo AML patients reported in only 1.6% (25/1546) of analysed cases.87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97 JAK2V617F mutations seem to cluster in AML with karyotypic aberrations. An incidence of 3.6% was found in CBF AML.97 Recent data suggest that JAK2V617F mutation may cooperate as class I mutation in leukemogenesis with t(8;21)/AML1-ETO, especially in therapy-related t(8;21)/AML1-ETO-positive AML.98 Besides, one case of de novo AML with a JAK2K607N mutation has been described.94 Two other JAK2-activating mutations, JAK2T875N and JAK2A572V, have been identified in megakaryoblastic leukemia cell lines.99 JAK2 mutations affecting exon 12 have recently been discovered in patients with JAK2V617F-negative PV or idiopathic erythrocytosis, but the existence of this type of mutation in AML has not been evaluated.100

Recently, gain-of-function mutations in the transmembrane domain of the thrombopoietin receptor (MPL), MPLW515L and MPLW515K, have been described in approximately 5% of MMM, 1% of ET and 2% (3/126) of AML cases.96, 101 Among AML patients, the 3 MPL mutants reported to date had AML following MMM. Expression of MPL515 mutant allele confers cytokine-independent growth and thrombopoietin hypersensitivity, and results in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these mutations may have functional complementation in myeloid disorders.96, 101

Inactivating mutations of c-CBL and CBL-b ubiquitin ligases, which are important regulators of RTK signaling, have recently been reported in AML. In particular, these mutations can upregulate the expression of FLT3 protein, suggesting a novel mechanism of FLT3 deregulation and leukemic transformation in AML. The prevalence and clinical significance of these mutations in AML remains to be determined.102, 103


Mutations that impair myeloid differentiation


The human AML1 gene (also named CBFA2 or RUNX1), located in 21q22 chromosomal band, encodes for one of the two subunits forming the human CBF.104, 105, 106 Expression of RUNX1 is controlled by two distinct promoters P1 and P2. During mouse embryogenesis the spatio-temporal expression of RUNX1 is developmentally regulated by alternative use of the two mutually distinct promoters, P1 and P2. These promoters, differentially regulated, allow the transcription of mRNAs with variant 5'-UTRs and the translation of structurally different protein isoforms showing the non-redundant function of P1 and P2.107 AML1 protein contains, in its N-terminal part, a highly evolutionary conserved domain of 128 amino acids called RUNT domain, responsible for both heterodimerization with the beta subunit of CBF and for DNA binding on the PEBP2beta sequence and a transactivation domain in C-terminal part.108, 109, 110 AML1 encodes three alternative spliced forms (AML1a, AMl1b and AML1c) which differ mainly in the C-terminal domain.111 These three isoforms have different and sometimes antagonist cellular functions. For example, AML1b can release myeloid cells from the AML1a-mediated differentiation block.112 AML1a can potentiate stem or progenitor cell engraftment, whereas AML1b has opposite effects. The expression of each isoform appears to be time dependent during embryogenesis but also in adult hematopoiesis.113 AML1 is normally expressed in all hematopoietic lineages and acts to regulate the expression of various genes specific to hematopoiesis, including M-CSF receptor, IL-3, myeloperoxydase and TCRbeta genes.114, 115, 116, 117 Mice lacking AML1 or CBFbeta have no fetal liver hematopoiesis, showing that the heterodimeric complex CBF is essential for definitive hematopoiesis of all lineages.118, 119, 120, 121

AML1 is one of the genes most frequently deregulated in leukemia mainly through chromosomal translocations, point mutations and amplifications. Chromosomal translocations involving AML1 gene occur in different leukemia subtypes, leading to the formation of fusion genes encoding for chimeric proteins, including AML1-ETO (t(8;21)) in AML, AML1-ETV6 (t(12;21)) in childhood acute lymphoblastic leukemia and less often AML1-MDS1 (t(3;21)) in MDS and blastic phase of chronic myeloid leukemia (CML), or other rare translocations.122, 123 Other mechanisms of AML1 inactivation have been reported in hematological malignancies, through point mutations, in AML and in MDS.124, 125, 126, 127, 128, 129 Both germ-line and acquired AML1 mutations have been reported in hematological malignancies. Germ-line mutations of the AML1 gene have initially been reported by Song et al. in very rare cases of familial platelet disorder with predisposition to AML (FPD/AML).130 Affected FPD/AML individuals had thrombocytopenia with platelet functional defects. In all cases, mutations were monoallelic and resulted in haploinsufficiency. Thus, loss of one AML1 allele appears sufficient for propensity to develop leukemia. Consistent with this observation, mouse embryos with hemizygosity for the mutant AML1 allele have an increased number of hematopoietic stem cells associated to a decrease in committed progenitors, suggesting that haploinsufficiency of AML1 affects maturation and proliferation of hematopoietic cells.131

On the other hand, acquired AML1 mutations are observed in 6–10% of sporadic AML and are found at similar frequency in adult and pediatric AML. Mutations are equally distributed between missense and nonsense mutations (resulting in truncated protein) in de novo AML. They occur mainly in the RUNT domain, located in the N-terminal part of the protein, and impair normal AML1 functions through the loss of transactivation and/or heterodimerization property. C-terminal mutations are seen at lower frequency and almost exclusively in MDS or AML following MDS, and seem to be associated with poor prognosis.132 A high frequency (40% ) of N-terminal AML1 mutation has also been observed in t-AML and t-MDS.132 Some monoallelic mutations may act in a dominant-negative manner through inhibition of the effects the remaining WT AML1. This hypothesis was confirmed by Osato et al. and Imai et al.,124, 126 who demonstrated that some AML1 gene missense mutation co-transfected with WT AML1 abolished transactivation of the M-CSF receptor promoter. Moreover, Imai et al.126 demonstrated that this dominant-negative effect was due to the fact that the mutated protein did not bind DNA but had enhanced capacity to bind CBFbeta and, by sequestering it, inhibited action of WT AML1, as observed for chimeric products of t(3;21) or t(8;21) translocations. AML1 point mutations predominate in M0 FAB subtype, where they are seen in 15–50% of cases and often biallelic mutations, inducing a total loss of function of AML1 gene.125, 128 Acquired AML1 mutations observed in other FAB subtypes are often monoallelic and often associated with acquired trisomy 21 or other cytogenetic abnormalities, such as trisomy 13, or with FLT3, P53 or N-RAS mutations.133, 134 Interestingly, in patients with constitutional trisomy 21 (that is, Down syndrome), who have a propensity to develop AML, no AML1 mutations have been found. Copy number variation of the AML1 gene could be presompted to participate to leukemogenesis both by increase or defect. Perhaps, gene dosage plays a role on P1 or P2 promoters recruitment or on the isoforms splicing. Those findings suggest that monoallelic mutations (except dominant-negative ones) are probably not sufficient to induce leukemia and that a second event, such as cytogenetic abnormalities or class I mutations affecting FLT3 or RAS genes is necessary.


The CEBPA gene, located on chromosome 19q13.1 band, belongs to the CCAAT/enhancer-binding protein family involved in the balance between cell proliferation and terminal differentiation. The CEBPA gene encodes a transcription factor playing a crucial role during differentiation of various cell types including hematopoietic cells. In hematopoiesis, CEBPA plays a pivotal role in early stages of myeloid differentiation and is particularly expressed in myelomonocytic cells.135, 136, 137 CEBPA acts in multiple ways: by down regulation of c-MYC expression allowing differentiation, by upregulation of the expression of granulocytic lineage-specific genes, and by synergistic action with other key genes involved in myeloid development, including CBF complex genes or PU.1.138, 139, 140 In addition to specific DNA binding, CEBPA could act by protein–protein interaction. The main partners of these interactions are p21, CDK2, CDK4 and E2F. CEBPA protein inhibits cell proliferation by activating transcription of p21/waf1, by stabilizating p21, by inhibiting CDK2 and CDK4.141, 142, 143 The CEBPA protein is a 42-kDa protein with four main domains: in the C-terminal part are a leucine zipper (bZIP) domain mediating homo- or hetero-dimerization and the DNA-binding domain, a basic positively charged domain able to interact with specific DNA sequences; in the N-terminal part of the protein are located two regulatory and transactivating domains, TAD1 and TAD2. The expression of CEBPA begins with the commitment of the myeloid lineage precursors and is upregulated during granulocytic differentiation. CEBPA-defective mice have no mature granulocytes, whereas cells of the other lineages are not affected.144 In addition, CEBPA expression could block monocytic differentiation.145

The implication of CEBPA in leukemogenesis has now been confirmed by many experiments. Pabst et al. found that events leading to the loss of CEBPA function facilitate leukemogenesis by blocking granulocytic differentiation in AML.146, 147, 148, 149 Three mechanisms of CEBPA inactivation have been reported: (1) downregulation of CEBPA expression consecutive to the AML1-ETO fusion transcript in t(8,21) leukemia cells, interestingly conditional expression of CEBPA in these cells is sufficient to trigger granulocytic differentiation;150 recently, Wouters et al. reported that the CEBPA gene could also be silenced by promoter hypermethylation in a specific subtype of AML that phenotypically showed aberrant expression of T-cell genes such as CD7 or enhanced expression of TRIB2, suggesting aberrantly activated NOTCH signaling.151 (2) Suppression of CEBPA function through inhibition of the translation of CEBPA mRNA by interaction with hnRNPE2, which is induced by BCR-ABL;152 this mechanism could explain transition of chronic phase to myeloid blast crisis in CML by blocking myeloid differentiation and (3) other genetic abnormalities affecting CEBPA gene, particularly mutations, which have been reported in hematological malignancies, mainly in AML.153

Acquired point mutations of the CEBPA gene have been reported in 89 of 965 (9% ) AML patients in 7 studies including 12 M0-AML, 159 M1-AML, 203 M2-AML, 44 M3-AML, 101 M4-AML, 98 M5-AML, 8 M6-AML, 4 M7-AML and 15 secondary AML and 321 AML for which FAB or WHO classification was not mentioned.146, 153, 154, 155, 156, 157, 158, 159, 160 CEBPA mutations can be divided into two main groups: N-terminal mutations that lead to increased translation of the alternative 30-kDa form with dominant-negative activity on the full-length 42-kDa protein; and C-terminal mutations that result in deficient DNA-binding and/or homodimerization activities. Some patients present a single CEBPA mutation, while some others have multiple alterations resulting from biallelic mutations or from several mutations on the same allele.153, 155, 159

In those studies, CEBPA gene mutations were frequent in M1, M2 and M4-AML (respectively, 19, 16 and 11% of mutated cases). The strong correlation between M1 and M2 FAB subtypes and CEBPA mutations (77% of AML with CEBPA mutation belong to these subtypes) supports the critical role of CEBPA gene in the intermediate stages of granulocytic differentiation. Patients with CEBPA mutations have distinct immunophenotypic features with a significantly higher frequency of the co-expression of CD7, CD34, HLA-DR and CD15.160 All but one of the reported patients with CEBPA mutations belonged to the 'intermediate' subgroup of the MRC cytogenetic prognostic classification, whereas no mutation was observed in the 'favorable' prognostic subgroup (that is, with translocation involving CBF genes or t(15;17)) and only one in the 'adverse' prognostic subgroup (complex karyotype: more than three abnormalities, del(5q)/-5, -7, 3q abnormalities), CBF AML were never associated with CEBPA mutations, showing that the above described mechanisms (1) and (3) that block differentiation of neutrophil granulocytes through CEBPA loss of function are mutually exclusive.

Four studies totaling 71 mutated cases versus 670 unmutated patients have evaluated the correlation between CEBPA mutations and other disease characteristics and prognosis.153, 154, 157, 158, 159, 160 No correlation was observed between CEBPA mutations and age, sex, WBC count, circulating blast count and platelet count. In the four studies, the CR rate was not significantly different in patients with or without CEBPA mutations. Nevertheless, in all but one of these studies, a correlation was found between CEBPA mutations and longer CRD or longer OS, reinforcing the association between event inducing loss of CEBPA function and favorable response to treatment.153, 155, 157, 159 Clinical data strongly support very favorable results with chemotherapy regimens containing high-dose AraC in AML patients with CEBPA loss of function. Analysis of cooperating mutations showed no difference in the incidence of FLT3 or MLL alterations between CEBPA-mutated and CEBPA nonmutated patients.157, 159 To note, germ-line mutation of CEBPA gene have been described in 10 cases of familial AML corresponding to 3 different families.161, 162, 163 All members affected by AML had a M1 or M2 FAB subtypes, as frequently observed in patients with somatic CEBPA mutations. Germ-line CEBPA mutations appear to be fully penetrant, since all mutated patients developed AML, and cause autosomal dominant inheritance of predisposition to AML.162 Within the three families reported, all members affected with AML harbored a germ-line CEBPA mutation that prevents the expression of the 42-kDa protein and results in truncated isoform with dominant-negative activity. At time of diagnosis, somatic C-terminal mutations of CEBPA gene were observed in the blast cells of the 10 patients, whereas 1 of the 5 remaining patients had an acquired trisomy 21.161, 162, 163 This observation supports that germ-line mutations in CEBPA predispose to AML and indicates that additional acquired CEBPA somatic mutations contribute to CEBPA loss of function, perhaps as a second event in the leukemogenesis.

Other mutated genes

Wilms' tumor 1 (WT1) gene, located at chromosome band 11p13, encodes a zinc-finger DNA-binding protein. Depending on the cellular context, it can be involved in transcriptional activation or repression. WT1 has a functional duality since it may act either as a tumor suppressor gene or as an oncogene. The precise role of WT1 in hematopoiesis and its contribution to leukemogenesis are still uncertain, although it has been suggested that impairment of WT1 protein function could promote stem cell proliferation and induce a differentiation block of hematopoietic cells.164, 165 WT1 gene is highly expressed in various types of leukemias, particularly in AML, and therefore can be used for MRD monitoring in AML patients. Mutations in WT1 gene in AML were first reported in 1998 by King-Underwood et al.166 in about 10–15% of AML cases. A recent study restricted to CN-AML confirmed this incidence and the association of WT1 mutations with failure to achieve CR with standard chemotherapy, in agreement with the results of the initial study.167 However, the poor prognostic impact of WT1 mutations needs to be evaluated in larger cohorts of AML patients.

PU.1 is a hematopoietic-specific Ets-family transcription factor required for normal blood cell development. It regulates a large number of target genes, including crucial myeloid genes, such as the granulocyte colony-stimulating factor (G-CSF) receptor, the M-CSF receptor and the GM-CSF receptor. To our knowledge, screening for PU.1 mutations has been performed in four main studies, including altogether 262 AML patients.168, 169, 170, 171 PU.1 mutations were found in only 9 of those 262 AML patients (all in the study by Mueller et al.168), showing that PU.1 mutations rarely contribute to AML pathogenesis.


Mutations of genes involved in cell cycle and apoptosis


Nucleophosmin (NPM1, also known as nucleolar phosphoprotein B23 or numatrin) is a ubiquitously expressed nucleolar phosphoprotein that continuously shuttles between the nucleus and cytoplasm with predominant nucleolar localization.172 NPM1 is a multifunctional phosphoprotein to which both tumor suppressor and oncogenic functions have been attributed, depending on gene dosage, expression levels, interacting partners and compartmentalization. NPM1 is a molecular chaperone that prevents protein aggregation in the nucleolus and regulates the assembly and transport of preribosomal particles through the nuclear membrane and DNA polymerase-alpha activity.173 It is a target of CDK2/cyclin E in centrosome duplication.174 NPM1 is also involved in cell cycle progression, response to stress and oncogenic stimuli and regulation of the alternate reading frame protein (ARF)-p53 tumor suppressor pathway at multiple levels175, 176, 177 and is required for the stabilization and the proper nucleolar localization of p14-ARF.178

The NPM1 gene, located at 5q35, is a partner in the chromosomal translocations of leukemias and lymphomas that result in fusion proteins containing only the NPM1 N-terminal region. A t(2;5)(p23;q35) translocation is observed in anaplastic large cell lymphomas and results in the chimeric fusion of NPM1 to ALK.179 The NPM1 gene also rearranges exceptionally with the retinoic acid receptor-alpha (RARalpha) in acute promyelocytic leukemia with variant t(5;17) translocation and with MLF1 in rare cases of AML and myelodysplasia with t(3;5)(q25.1;q34) translocation.180, 181

More recently, mutations in exon 12 of the gene encoding NPM1 have been described in AML.182 More than 95% of the mutations consist of a 4-bp insertion at position 960. Mutation A, due to a TCTG duplication, accounts for 70–80% of adult cases and mutation B and D together for 15–20% . About 40 different variant mutations have been identified to date. All cases are heterozygous for the mutation and retain the WT allele.6, 11, 12, 182, 183, 184 Despite the heterogeneity of NPM1 mutations, all variants cause frameshifts in the region encoding the C-terminal region of the NPM1 protein. As a consequence, abnormal proteins have acquired, at the C terminus, an additional nuclear export signal motif and have lost both tryptophan residues 290 and 288 (or only tryptophan 290), which determine nucleolar localization. This molecular mechanism is responsible for the aberrant cytoplasmic localization of NPM1-mutated protein, which can easily be detected by immunohistochemistry. The cytoplasmic localization of NPM1-mutated protein is probably critical for its putative role in leukemogenesis. NPM1 mutations have been found nearly exclusively in de novo AML with an incidence of approximately 30% in adults, and not in secondary AML, thus becoming the most frequent genetic lesions in adult de novo AML. NPM1 mutations have been found to occur in an age-dependent fashion with significantly higher incidence in older compared to younger adults.182, 184 Their incidence is however much lower in children than in adults (about 2–6% ).185, 186 NPM1 mutations are associated with all morphological FAB subtypes (except M3) with highest frequency in M4/M5 AML. NPM1 mutations are significantly associated with higher initial WBC count, higher BM blast count as well as higher platelet count, female gender and low CD34 expression levels on blasts.12 Except for five cases reported, no NPM1 mutations have been reported in AML with recurrent translocations t(8;21), inv(16) and t(15;17).12, 187 In cases with complex karyotype or diverse cytogenetic abnormalities, NPM1 mutations are also rare.12 NPM1 mutations occur predominantly in CN-AML: about 50% of CN-AML are NPM1 mutated and 85% of NPM1-mutated AML are CN-AML.187 NPM1 mutations are significantly correlated with FLT3-ITD, FLT3-TKD mutations and in some series with a decreased prevalence of CEBPA mutations and MLL-PTD.6, 11, 12, 182, 183, 184 The frequency of c-KIT and N-RAS mutations does not differ in mutated and WT NPM1 AML.6, 187 Within CN-AML, NPM1-mutated AML show a distinct gene-expression profile (GEP) characterized by upregulation of genes involved in stem-cell maintenance including an overexpression of HOX genes (HOXA, HOXB).184, 188 Patients with intermediate cytogenetic risk AML NPM1-mutated/FLT3-ITD negative have a significantly better response to induction therapy, better EFS and better OS than those without NPM1 mutation. Indeed, NPM1 mutations predict favorable outcome in CN-AML only in the absence of FLT3-ITD.6, 12, 182, 183, 184 Döhner et al.171 found that NPM1-mutated/FLT3-ITD-negative patients had a 5 years survival probability of approximately 60% , comparable to those of patients with either CBF AML or CN-AML with CEBPA mutations. In a donor versus no donor comparison, NPM1-mutated/FLT3-ITD-negative patients did not benefit from allogenic stem cell transplantation.183 NPM1 mutations seem to be relatively stable during disease evolution. Of the 32 cases sequentially studied and published so far, patients who had NPM1 mutation at diagnosis all still carried the same mutation at relapse, except 3 who lost the mutation (but this change was associated with the emergence of new cytogenetic abnormalities in 2 of them). Besides, in all NPM1 WT patients studied at diagnosis, none acquired NPM1 mutation at relapse. Clearly, the stability of NPM1 mutations during follow-up needs to be confirmed in a large cohort of paired AML patients who relapse.11, 186, 187, 189

TP53 gene

The TP53 gene is a tumor suppressor gene located in 17p13 that acts as the 'guardian of the genome'.190, 191 Many diverse cellular events, including DNA damage and hypoxia, activate the TP53 gene. The P53 protein functions as a transcription factor, regulating downstream genes involved in cell cycle arrest, DNA repair and programmed cell death.191, 192, 193 Loss of P53 function confers genomic instability, impaired apoptosis and diminished cell cycle restraint.194, 195, 196, 197, 198, 199 In AML, P53 can be inactivated by deletion or point mutations, which are generally missense mutations, involving almost exclusively exons 4–8 of the gene.200 P53 gene mutations are found in less than 10% of de novo AML.200, 201 In de novo AML, single-base substitutions at G-C pairs represent the most frequent mutations, but, compared with t-AML and other hematological malignancies or solid tumors, the mutational spectrum does not show a unique pattern.202, 203 P53 mutations are generally associated to 17p deletion, generally through unbalanced translocations such as t(5;17), therefore resulting in inactivation of both TP53 alleles (one through point mutation, the other through deletion). TP53 mutations are also closely related to older age, to deletion or loss of 5q, of 7q and complex karyotypes.200, 204 Patients with TP53 mutation are generally resistant to chemotherapy and have very short survival.205

The frequency of P53 mutation is higher in t-MDS and t-AML, since about 30% of P53-mutated cases occur after previous chemotherapy with alkylating agents, platinum derivatives or topoisomerase II inhibitors.204, 206 In addition, the type of mutations is different between de novo and therapy-related mutations, with a higher frequency of A-T transversion in therapy-related cases and G-C mutation in de novo cases.204 A strong correlation between P53 mutations associated to loss of heterozygosity (LOH) and a typical form of dysgranulopoiesis combining pseudo-Pelger-Huët hypolobulation and small vacuoles in neutrophil granulocytes has been reported in AML and MDS.207, 208 Detection of P53 mutations is important because, in patients with LOH, response to chemotherapy will be extremely short and, in those cases, allogenic bone marrow transplantation should be considered.204



Clinicobiological features and prognostic significance of the main gene mutations implicated in AML are summarized in Table 1. The screening of these mutations is of great interest for the understanding of AML pathogenesis and also for the management of AML patients.

Cooperation between gene mutations

The first question is why so many mutational events are found in AML and how they cooperate in the disease pathogenesis? Instability in the genome of blast cells is now clearly suspected in the pathogenesis of AML. Those perturbations probably result from deregulation of genes involved in cell maintenance and DNA repair. Such instability leads to acquisition of additive molecular abnormalities that contribute to disease progression.209, 210 A mechanism of multistep leukemogenesis is in agreement with this hypothesis, particularly in AML, where a combination of events leading to cell proliferation with events leading to block myeloid differentiation (so-called type I mutations and type II mutations, respectively) is strongly suspected.1, 211, 212 Due to their prognostic value, the mutational events screening is particularly important in CN-AML patients.

Alcalay et al.210 have shown that these AML fusion proteins, which are especially known to block myeloid differentiation (including AML1-ETO, PML-RARA and PLZF-RARA), deregulate genes involved in stem cell maintenance and DNA repair. Thus, chimeric oncoproteins increase the rate of secondary mutations. Some AML fusion proteins have been shown to induce a mutator phenotype in blast cells. As an example, transfection of PML-RARA or AML1-ETO fusion protein in U937 cell line can induce a significant reduction of DNA repair of the damage induced by methanesulfonate, particularly through down regulation of the expression of seven genes (ADPRTL2, FEN1, OGG1, MPG, LIG3, POLD2 and POLD3) involved in base excision repair.210 Moreover, a preferential association between one type of class I mutations and some fusion proteins has been observed, for example between c-KIT or RAS mutations and CBF AML. A cooperation between class I mutations and AML1 mutations has also been reported in AML, which supports this hypothesis that mutations affecting AML1 can reproduce those effects.211, 212 The parallel mutational analysis of genes involved in signal transduction pathways (FLT3, RAS, PTPN11) and in myeloid differentiation (AML1, CEBPA) should help clarify this hypothesis. Based on the two-hit model of AML pathogenesis, the frequent association between NPM1 and FLT3-ITD mutations argues for a role of NPM1 in hematopoietic differentiation. The absence of preferential association between CEBPA mutations and class I mutations does not go along this hypothesis. However, it is likely that other molecular abnormalities affecting proliferation pathways will be discovered, so that the existence of the two complementation groups cannot be excluded.

Other mechanisms of leukemogenesis appear to arise from an underlying mutator phenotype associated to the history of the disease or to a particular genetic background (predisposition to acute leukemia seen in FPD, Down syndrome or familial form of CEBPA mutations). In those situations, is the two-hit model relevant? If yes, this suggests that class II mutations preexist to class I mutations. The concept of LSC also supports the hypothesis that class I mutations are secondary to class II mutations.213, 214 In agreement with this hypothesis is that some patients with FLT3 mutation at diagnosis relapse without mutation.26, 44

Another event implicated in leukemogenesis is the deregulation, in blast cells, of genes involved in the maintenance of the stem cell phenotype.215 In AML blast cells, the machinery promoting ability to self-renewing divisions induces an expansion of a compartment of true LSC.215 The expansion of this compartment increases the likelihood of molecular alterations which contribute to the transformation of those cells. GEP analysis of AML samples clearly shows down regulation of genes involved in differentiation (CEBP family, JUN family, CSF3R, ELF4, STAT5...) and upregulation of genes involved in stem cell maintenance phenotype including BCL1, LMO1 and JAG1.215, 216, 217, 218, 219 It has been reported that AML-specific fusion proteins including AML1-ETO and PML-RARA induce NOTCH signaling pathway through the induction of JAG1 leading to self autonomous self renewal abilities of blasts. Moreover, GEP unsupervised clustering clearly separated NPM1 mutated from NPM1 WT AML, regardless of the presence of FLT3 mutations or non major chromosomal rearrangements, supporting the concept that NPM1-mutated AML represent a distinct entity.188 The GEP signature of NPM1-mutated AML shows upregulation of genes involved in the maintenance of a stem-cell phenotype, including the same NOTCH JAG1 pathway. Among the genes upregulated are numerous members of the homeodomain-containing family of transcription factors, including HOX (that are highly expressed in hematopoietic stem cells).219 Acute leukemias carrying MLL rearrangements also display induction of HOX genes, possibly due to direct binding of MLL fusion proteins to HOX promoters.220 Such LSC can be triggered to proliferate after class I mutations.

Role of gene mutations screening in the practical management of AML patients

Cytogenetic analysis at time of diagnosis constitutes a major prognostic factor in clinical outcome in AML, which identifies subgroups of favorable, intermediate and 'unfavorable' prognosis. Nevertheless, clinical evolution in those three subgroups remains very variable, particularly for CN-AML.

In this last group, identification of FLT3-ITD mutation probably constitutes the most important known pretreatment prognostic factor. There is a general agreement that the presence of FLT3-ITD mutation is associated with a higher risk of relapse, and it constitutes for many groups an indication to proceed to bone marrow transplantation if a donor is available, although this is controversial for other groups.36 NPM1 mutations are also emerging as a second gene mutation known to have clinical relevance in CN-AML. However, their favorable prognostic value is only observed in patients without FLT3-ITD. Besides, several studies have provided important evidence that CEBPA mutation represents also an independent positive prognostic factor in CN-AML. Therefore, NPM1 and CEBPA mutational status are starting to be used for treatment stratification in new clinical trials.

In CBF AML, many studies support that additional FLT3-ITD or c-KIT mutations constitute factors associated with an increased risk of relapse. Screening for FLT3-ITD and c-KIT mutations is therefore useful to identify patients who may benefit from bone marrow transplantation and/or alternative strategies including new targeted therapies. A classification of AML combining cytogenetic and molecular findings would allow more accurate prediction of the response to therapy and thereby the selection of more appropriate treatments, especially in patients with CN-AML or CBF AML.

Practical guideline for the mutational screening in AML patients

On the basis of those findings, we proposed a schema for molecular screening in AML patients in routine practice represented in Figure 1, according to the frequency of each mutation and to their clinical significance. This guideline aims at showing which gene mutations should be investigated in a particular cytogenetic subgroup. To note that it is valuable only in the state-of-the-art of conventional chemotherapy regimen currently used in AML.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Proposed schema for molecular screening in AML patients in routine practice, depending on a cytogenetic prescreening. Step 1: cytogenetic analysis, including karyotype and FISH analysis for screening of MLL rearrangements, is performed. In case of CBF AML or AML with intermediate karyotype, molecular analysis is required to refine prognosis. In the remaining cytogenetic subsets, namely AML with t(15;17) or unfavorable karyotype, molecular analysis is not particularly indicated. Step 2: within CBF AML and AML with intermediate karyotype, mainly CN-AML, screening of gene mutations with well-established prognostic significance is recommended, i.e., FLT3-ITD and c-KIT mutations, and FLT3-ITD, NPM1 and CEBPA mutations, respectively. Step 3: screening of other molecular alterations with potential clinical relevance within CBF AML or CN-AML subsets may help to refine prognosis. The percentages indicated correspond to the average proportion of mutated patients in each subgroup. AML, acute myeloid leukemia; CBF, core binding factor; CN-AML, cytogenetically normal AML; ITD, intern tandem duplication; TKD, tyrosine kinase domain; PTD, partial tandem duplication.

Full figure and legend (147K)

In AML with intermediate karyotype, and particularly in CN-AML, the poor prognosis of FLT3-ITD is only modestly influenced by the concomitant presence of favorable molecular markers identified so far, such as NPM1 and CEBPA mutations. However, given the frequent association and the prognostic interaction between FLT3-ITD and NPM1 mutations, both alterations should be tested together in all patients with CN-AML. Furthermore, NPM1 mutations could become relevant in FLT3-ITD-positive patients treated with FLT3 inhibitors, when those drugs are available. If NPM1 and FLT3-ITD mutations are both negative, CEBPA mutations should be tested for further risk stratification. Lastly, screening of other gene mutations with potential clinical relevance, such as FLT3-TKD, MLL-PTD, RAS and WT1 mutations, as well as overexpression of genes like EVI1, ERG, MN1 or BAALC, may help refine prognosis. However, it has not yet been firmly established if the overexpression of EVI1, ERG, MN1 or BAALC genes provides an independent poor prognostic factor.

In CBF AML, screening of FLT3-ITD and c-KIT mutations should be performed systematically in each case for therapeutic stratification and potential use of TKIs. RAS and FLT3-TKD mutations can also be tested in CBF AML, but their clinical impact in those patients needs to be further investigated.

In the remaining subgroups, namely AML with unfavorable karyotype and AML with t(15;17), mutational screening is not particularly recommended since gene mutations have no significant prognostic relevance with current treatment modalities. In acute promyelocytic leukemia, the negative impact of FLT3-ITD on prognosis appears to be redundant to that of increased WBC count, but the analysis of FLT3-ITD status may be helpful for the future use of FLT3 inhibitors.

Gene mutations as potential markers for MRD monitoring

Detection of MRD is of growing importance in the management of AML patients. In AML with balanced chromosomal translocations, evaluation of MRD is possible using the fusion transcripts corresponding to inv(16)/t(16;16), t(8;21), t(15;17) and MLL rearrangements, which are detectable by real-time quantitative polymerase chain reaction (RQ-PCR). In the other cases, representing approximately 70% of AML patients, MRD monitoring is hampered by the lack of reliable molecular markers. For that reason, the use of WT1 gene expression and gene mutations for PCR-based MRD detection has been proposed. FLT3-ITD and NPM1 mutations are potentially good candidates for this purpose, since they are applicable to about 30 and 50% of CN-AML, respectively. RQ-PCR techniques using a mutation-specific primer have been developed for both mutations and permit to reach a high sensitivity (about 10- 4 for FLT3-ITD mutations, and 10- 4 to 10- 5 for NPM1 mutations). However, the suitability of FLT3-ITD mutations as MRD marker remains controversial because of their relative instability during follow-up and their variability from a patient to another and sometimes during disease progression in the same patient.26, 44, 46 In addition, RQ-PCR assays based on FLT3-ITD mutations are not without limitations, including the difficulty to sequence the duplicated fragment in cases with low mutated/WT ratio and the requirement for optimal patient-specific primers and probe. FLT3-ITD mutation can still be valuable in case it is the only marker available for MRD follow-up, but should be used with caution as early predictor of relapse. In this respect, the use of several markers in combination, for example FLT3-ITD mutation associated with WT1 gene expression or NPM1 mutation, can be helpful to avoid false negative results. Compared to FLT3-ITD mutations, NPM1 mutations seem to be more stable during disease evolution.11, 186, 189 Another advantage of NPM1 mutations is that the most frequent variants (A, B and D) account for over 90% of all NPM1 mutations, thus making easier the routine detection of MRD. Besides, NPM1-MRD levels seem to correlate with response to therapy and clinical status.189 However, even if those results are encouraging, the use of FLT3-ITD and NPM1 mutations as MRD markers needs to be validated in large prospective clinical trials. Further studies will determine if these assays will serve to predict outcome and help risk stratification in CN-AML.189

Gene mutations as potential therapeutic targets

Many of the identified gene mutations that affect proliferation pathways represent potential targets for the development of new drugs. These targeted therapies could be used as single agent or in combination with conventional chemotherapy in AML. In such a way of evaluation of novel therapeutic approaches, a complete screening of all mutations mentioned above, as well as GEP analysis, should be performed to detect the main predictive factors of response to therapy.

Optimal treatment for CN-AML patients with FLT3-ITD mutations is yet unclear. It has been reported that bone marrow transplantation in first CR may not overcome the chemoresistance/radioresistance inherent in FLT3-ITD-positive blasts.5, 36 Therefore, FLT3-ITD-positive patients could also potentially benefit from treatment with FLT3 inhibitors. Several small molecule TKI with activity against FLT3, such as PKC412 (midostaurin), CEP-701 (lestaurtinib), SU11248 (sunitinib) or MLN518 (tandutinib), are currently in clinical phase I and II trials. In patients with FLT3-ITD or FLT3-TKD mutations treated with TKI alone, clinical responses are usually manifested as a transient reduction in blood and, less frequently, in bone marrow blasts. Few patients achieve a CR rate or prolonged partial response. Several trials combining TKI and conventional chemotherapy are ongoing in patients with newly diagnosed FLT3-mutant AML or in AML in relapse.221, 222, 223, 224, 225, 226, 227, 228, 229 TKI may also target c-KIT mutations, although in such cases the exact location and nature of the mutation must be determined individually because specific inhibitors are active against particular c-KIT mutations. For example, cells carrying insertion/deletion in exon 8, ITD of exon 11 and 12 or substitutions at codon 822 are sensitive to imatinib, while D816 mutations confer a resistance to imatinib but can be targeted with other TKI such as midostaurin, nilotinib or dasatinib.54, 58, 64, 230, 231, 232, 233 Therefore, testing for c-KIT mutations should be performed in all CBF AML patients for risk-adapted treatments.

RAS proteins require post-translational modification by farnesylation to be biologically active. Farnesyl transferase inhibitors have some antitumor activity in the clinic in AML, but they also seem to act through targets other than RAS. Several compounds that block specifically RAS pathway are currently being tested in AML.234

Lastly, emerging epigenetic therapies combining hypomethylating agents, including 5-azacytidine and decitabine, to histone deacetylase (HDAC) inhibitors, such as valproic acid (with or without all-trans retinoic acid) or more recently designed compounds, appear promising. This new approach has recently shown particular interest in AML patients with MLL-PTD, where this combination was found to reactivate the transcription of MLL WT allele, and this was associated with enhanced cell death of MLL-PTD-positive leukemic blasts. These data may provide a rationale to evaluate treatment with DNA methyltransferase and HDAC inhibitors in patients with MLL-PTD.235



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