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Genomic profiling of high-risk acute lymphoblastic leukemia


Acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising multiple subtypes with different genetic alterations and responses to therapy. Recent genome-wide profiling studies of ALL have identified a number of novel genetic alterations that target key cellular pathways in lymphoid growth and differentiation and are associated with treatment outcome. Notably, genetic alteration of the lymphoid transcription factor gene IKZF1 is a hallmark of multiple subtypes of ALL with poor prognosis, including BCR-ABL1-positive lymphoid leukemia and a subset of ‘BCR-ABL1-like’ ALL cases that, in addition to IKZF1 alteration, harbor genetic mutations resulting in aberrant lymphoid cytokine receptor signaling, including activating mutations of Janus kinases and rearrangement of cytokine receptor-like factor 2 (CRLF2). Recent insights from genome-wide profiling studies of B-progenitor ALL and the potential for new therapeutic approaches in high-risk disease are discussed.


Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer and an important cause of morbidity and mortality from hematopoietic malignancies in adults.1, 2 Despite impressive advances in the outcome of therapy of childhood ALL in the last five decades, with cure rates now exceeding 80%,3, 4 relapsed ALL remains a leading cause of cancer-related death in children and young adults.5, 6, 7 Moreover, with increasing age through adolescence and adulthood, cure rates for ALL fall sharply, and the genetic and biological determinants of treatment failure remain incompletely understood.8, 9

ALL is characterized by recurring genetic alterations, including chromosomal aneuploidy (high hyperdiploidy and hypodiploidy), and a number of chromosomal rearrangements that dysregulate hematopoietic regulators, transcription factors and tyrosine kinases (for example, ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, rearrangement of MLL and rearrangements of T-cell receptor genes to hematopoietic regulators and transcription factors in T-lineage ALL).10, 11 Although alterations associated with favorable outcome (for example, high hyperdiploidy and ETV6-RUNX1) are characteristic of childhood ALL, and the frequency of BCR-ABL1 (Philadelphia chromosome positive, or Ph+) ALL rises with age,12 the differences in the frequencies of these recurring gross chromosomal rearrangements is insufficient to fully explain treatment failure in ALL, which occurs across the spectrum of cytogenetic subtypes, including cases that lack cytogenetic alterations. Consequently, there has been great interest in using genome-wide approaches to identify submicroscopic genetic alterations in ALL, and these studies have proven exceptionally fruitful in identifying new mutations that target key cellular pathways in B-progenitor and T-lineage ALL. These studies have been reviewed recently in the journal and elsewhere (see Mullighan and Downing13, 14), and are summarized to provide context for recent studies of high-risk ALL. Although these studies have also been informative in T-lineage ALL,15, 16, 17, 18 this review focuses primarily on B-progenitor ALL and recent studies that have identified genetic markers of treatment failure in ALL.

The spectrum of genetic alterations in ALL

Multiple groups have used high-resolution microarray platforms, including single-nucleotide polymorphism microarrays and oligonucleotide array-Comparative Genomic Hybridization, to profile genetic alterations at high resolution in B-progenitor and T-lineage ALL. The majority of these studies have examined pediatric ALL, and high-resolution studies profiling genetic alterations in large cohorts of adult ALL are required, but at present are lacking (Table 1). Despite a relatively low average number of DNA copy number alterations compared with many solid tumors19—approximately six to eight lesions per case15, 20—these studies have identified multiple novel genetic alterations targeting key cellular pathways and genes known to have key roles in leukemia development.15, 21, 22 These include transcriptional regulators of lymphoid development (for example, PAX5, IKZF1 and EBF1), cell cycle regulators and tumor suppressor genes (CDKN2A, CDKN2B, RB1 and PTEN), lymphoid signaling genes (CD200, BTLA and BLNK) and drug response genes (for example, the glucocorticoid receptor gene NR3C1). A striking finding from these studies is that genes regulating B-lymphoid development are mutated in the majority of B-progenitor ALL cases, most commonly deletions, sequence mutations or translocations of PAX5,15, 21, 22, 23 deletion (and, less commonly, sequence mutation) of IKZF1 (IKAROS) and the IKAROS family members IKZF2 (HELIOS) and IKZF3 (AIOLOS) and deletion of EBF1. These mutations result in loss of function in vitro,15 and accelerate the onset of ALL in murine models of ALL.24, 25, 26 Although the mutations most commonly involve only a single copy of the affected gene, multiple mutations involving this pathway are common in high-risk B-ALL, and a higher number of lesions in the pathway is associated with poor outcome,27 suggesting the degree of ‘block’ in B-cell differentiation induced by mutations in this pathway contributes to not only leukemogenesis but also treatment responsiveness.

Table 1 Details of studies reporting alterations of IKZF1, Janus kinase genes and CRLF2 in lymphoid leukemia

Genomic profiling of high-risk ALL—a central role of IKZF1

An additional important observation was that the frequency and type of submicroscopic genetic alterations was strongly associated with ALL subtype. Notably, MLL-rearranged ALL cases harbor fewer than one copy number alteration per case, suggesting that few cooperating structural genetic alterations are required to induce leukemia.15, 28 In contrast, ETV6-RUNX1 and BCR-ABL1 (Ph+) ALL cases harbor multiple distinct copy number alterations.15, 29 Deletion of IKZF1 (IKAROS) is a hallmark of Ph+ lymphoid leukemia, including both childhood and adult de novo ALL cases20, 30 and chronic myeloid leukemia at progression to lymphoid blast crisis20, 30 (Table 1). Moreover, the presence of IKZF1 alterations is associated with poor outcome in Ph+ ALL.31 IKAROS is a member of a family of zinc-finger transcription factors that has complex, context-dependent functions, including transcriptional regulation and chromatin remodeling, and is required for the development of all lymphoid lineages.32, 33, 34, 35, 36, 37 Expression of aberrant IKAROS isoforms in ALL blasts had been recognized for many years, particularly one isoform, IK6, which lacks the N-terminal zinc fingers of IKAROS and cannot bind DNA, but retains the C-terminal zinc fingers and can act in a dominant-negative manner.38, 39, 40 Before detailed DNA copy number analyses of ALL, the factors determining expression of these aberrant IKZF1 isoforms had been unclear, and post-transcriptional mechanisms induced by BCR-ABL1 had been suggested.40, 41 However, single-nucleotide polymorphism array profiling studies of both ALL and chronic myeloid leukemia have shown that expression of these dominant-negative transcripts is determined by the presence of IKZF1 deletions that involve the exons corresponding to those deleted in the aberrant IKZF1 transcripts and IKZF1 protein.20, 30

Alterations in IKAROS function have an important role in the pathogenesis of lymphoid tumors. Mice harboring a dominant-negative mutation in the Ikzf1 gene develop an aggressive T-lineage lymphoproliferative disease.42 The role of IKAROS in the pathogenesis of Ph+ ALL remains to be fully defined. However, existing data have shown that expression of IK6 impairs B-lymphoid maturation43, 44 and pre-B-cell receptor signaling in Ph+ ALL cells.45 Moreover, deletion of Ikzf1 accelerates leukemogenesis in a murine model of Ph+ ALL.26

A role for IKAROS in the pathogenesis of ALL is also supported by recent data from genome-wide association studies in which an inherited single-nucleotide polymorphism allele at the IKZF1 locus was associated with the risk of childhood ALL, a finding that has been identified in multiple studies and patient cohorts.46, 47, 48 The mechanistic basis of this finding remains unclear, although it is notable that IKZF1 genotype was associated with the level of gene expression,46 and the genes at the two other loci found to be associated with ALL risk in these studies, ARID5B and CEBPE, also encode transcriptional regulators and genes involved in lymphoid maturation,49, 50 suggesting that germline variation at these loci directly influences the risk of ALL.

Recent studies have also shown that alterations of IKZF1 are associated with poor outcome in Ph− ALL. In a study of over 200 cases of high-risk B-progenitor Ph−ALL (the Children's Oncology Group P9906 study), genome-wide profiling of DNA copy number alterations and gene expression profiling, together with candidate gene resequencing, identified IKZF1 deletions and sequence mutations in approximately one-third of cases (Figures 1a and b), and was associated with a near tripling of the risk of treatment failure27 (Figure 1d). This strong association between IKZF1 and adverse outcome was confirmed in the Dutch DCOG-ALL9 cohort.51 In addition, profiling of serial ALL samples has identified substantial differences in the genetic alterations present at diagnosis and relapse. However, IKZF1 alterations are almost always preserved from diagnosis to relapse, and may also be acquired as a new lesion at relapse.52, 53, 54 Together, these findings add weight to the findings from studies of Ph+ leukemia that alteration of IKZF1 is a key determinant of leukemogenesis and response to therapy.

Figure 1

IKZF1 (IKAROS) alterations in ALL. (a) dChip DNA copy number heat map showing focal and broad IKZF1 deletions in ALL. Deletions are shown as blue. (b) Sequence mutations of IKZF1 and alignment with IKZF1 domains. IKAROS has four N-terminal zinc fingers that mediate DNA binding, and two C-terminal zinc fingers that mediate dimerization (green). The dominant-negative isoform IK6 lacks the N-terminal zinc fingers and the ability to bind DNA. (c) Gene set enrichment analysis showing similarity of the gene expression profiles of Ph+ ALL, and Ph− IKZF1-deleted, high-risk ALL. The red curve in the left panel is the enrichment curve, which is a running measure of similarity of the gene expression signatures. The heat map shows the gene expression data for the high-risk ALL signature in a spectrum of childhood ALL cases and the similarity to BCR-ABL1-positive ALL. (d) Association between IKZF1 alteration and poor outcome in two cohorts of childhood ALL. Abbreviations: B-A, BCR-ABL1 positive; hypo, hypodiploid; H50, hyperdiploidy with greater than 50 chromosomes; E-R, ETV6-RUNX1; T-P, TCF3-PBX1. Adapted from Mullighan et al.27

An additional observation from the COG P9906 study was that the gene expression profile of the poor-outcome, IKZF1-altered cases was strikingly similar to that of Ph+ ALL27 (Figure 1c). A similar subtype of ‘BCR-ABL1-like’ ALL enriched for genetic alterations targeting B-lymphoid development has also been described by Den Boer et al.55 The similarity of the gene expression profiles of IKZF1-deleted Ph+ and Ph− ALL suggests that perturbation of IKZF1 activity may directly influence the leukemic transcriptome and the degree of differentiation of ALL cells. Consistent with this, the gene expression profile of IKZF1-mutated Ph− ALL exhibits enrichment for hematopoietic stem cell genes and reduced expression of B-cell signaling genes.27 An additional potential explanation is that IKZF1-mutated, BCR-ABL1-like cases harbor mutations that result in activation of downstream signaling pathways similar to those activated by BCR-ABL1, and recent data have shown that this indeed is the case. A substantial proportion of BCR-ABL1-like ALL cases have genetic alterations that result in aberrant cytokine receptor signaling, notably activating Janus kinase (JAK) mutations and rearrangement of cytokine receptor like factor 2 (encoding the lymphoid cytokine receptor gene CRLF2).

Genetic characterization of BCR-ABL1-like, Ph− ALL

Genomic resequencing of targets of DNA copy number alteration, dysregulated gene expression, and a subset of receptor and non-receptor tyrosine kinases in 187 high-risk B-progenitor ALL cases from the Children's Oncology Group P9906 cohort described above27 identified 20 cases with somatic mutations in JAK1, JAK2 and JAK3.56 The mutations were most commonly at or near R683 in the pseudokinase domain of JAK2, but were also found in the kinase domain of JAK2 and the pseudokinase domain of JAK1. Notably, the V617F mutation commonly observed in the myeloproliferative disorders57, 58, 59, 60 has not been identified in B-progenitor ALL, although the homolog of JAK2 V617F, JAK1 V658F, has been identified.61 The presence of JAK mutations was associated with IKZF1 mutations, a BCR-ABL1-like gene expression profile, and poor outcome. Notably, JAK2 mutations (again, most commonly at R683 in the pseudokinase domain) had also recently been reported in up to one-quarter of cases of B-progenitor ALL associated with Down's syndrome62, 63, 64 (Table 1); however, most cases in the P9906 high-risk ALL cohort with JAK mutations were cases not associated with Down's syndrome. JAK1 pseudokinase mutations have also been described in T-lineage ALL, albeit more commonly in adults than in children.61, 65 The frequency of JAK2 mutations in large cohorts of adult ALL cases has not been determined. Similar to the JAK2 V617F mutation, the JAK1 and JAK2 mutations observed in ALL are transforming in vitro, conferring cytokine-independent growth and constitutive Jak–Stat activation when introduced into Ba/F3 cells (a murine pro-B-cell line) expressing the erythropoietin or thrombopoietin receptors.56, 63, 66

The JAKs are key mediators of hematopoietic cytokine receptor signal transduction.67, 68, 69 The identification of distinct JAK mutations in myeloproliferative diseases and ALL suggested that different mutated JAK alleles may interact with different downstream signaling pathways and influence the disease lineage. Recent studies have shown that the presence of JAK mutations in ALL are associated with chromosomal alterations, resulting in overexpression of the cytokine receptor CRLF2 (or thymic stromal lymphopoietin receptor), highlighting a new pathway of perturbed lymphoid signaling in ALL.

Single-nucleotide polymorphism array profiling of the high-risk pediatric ALL cohort described above demonstrated that many of the JAK-mutated cases harbored focal DNA copy number alterations, most commonly interstitial deletions, involving a cluster of hematopoietic cytokine receptor genes including IL3RA (interleukin 3 receptor alpha) and CSF2RA (GM-CSF receptor) at the pseudoautosomal region 1 (PAR1) at Xp/Yp (Figures 2a and b). These alterations were adjacent to the CRLF2 locus at PAR1, and were associated with markedly elevated expression of CRLF2.70 Notably, Russell, Harrison and colleagues had also identified dysregulated expression of CRLF2 arising from rearrangement of CRLF2 into the immunoglobulin heavy chain locus (IGH@-CRLF2), or associated with the PAR1 deletion, in a subset of B-progenitor ALL.71 Defining the precise limits of the PAR1 deletion was difficult due to poor microarray probe coverage of the PAR1 region, but mapping using high resolution microarrays and long range genomic PCR showed that the deletion extended from intron 1 of P2RY8 (encoding the purinergic receptor gene P2Y, G-protein coupled, 8) to immediately upstream of the first coding exon of CRLF2.61 The deletion breakpoints were tightly clustered and resulted in a novel fusion transcript, P2RY8-CRLF2, in which the first, non-coding exon of P2RY8 is fused to the entire coding region of CRLF2 (Figures 2c and d). This rearrangement appears to represent a form of ‘promoter swapping’. P2RY8 is a member of a family of purinergic receptor genes that is expressed in hematopoietic cells, including leukemic blasts, and has previously been identified as a rare target of translocation to SOX5 in lymphoma.72

Figure 2

CRLF2 and JAK alterations in ALL. (a) Focal deletions in the pseudoautosomal 1 region of Xp/Yp in ALL. (b) Mapping of the PAR1 deletion (probe-level data are shown as vertical red lines) to the region between intron 1 of P2RY8 and upstream of CRLF2. (c–e) The PAR1 deletion results in P2RY8–CRLF2 fusion that may be detected by RT-PCR (c, d) and by immunophenotyping of leukemic cells (e). (f, g) Expression of mutated Jak alleles and P2RY8-CRLF2 in Ba/F3 cells expressing the IL-7 receptor results in constitutive Jak–Stat activation, shown in panel (f) by western blotting. Two examples of JAK2 mutant alleles are shown: the R683G mutation in the JAK2 pseudokinase domain and the P933R mutation in the kinase domain. (g) Expression of JAK2 mutations and P2RY8-CRLF2 results in transformation of Ba/F3-IL7R cells to cytokine-independent growth. (h) Cytokine-independent growth of Ba/F3-IL7R cells transformed by P2RY8-CRLF2 and JAK mutations (JAK2 P933R, blue line; R683G, red line) is attenuated by pharmacological JAK inhibitors. Abbreviations: B7, Ba/F3-IL7R; H47, low hyperdiploid ALL; hypo, hypodiploid; P2C, P2RY8-CRLF2; WT, wild type. Data taken from Mullighan et al.61

CRLF2 alterations in B-progenitor ALL have been subsequently confirmed and identified by multiple groups, including adult ALL61, 70, 71, 73, 74 (Table 1). CRLF2 is rearranged in five to seven percent of B-progenitor childhood ALL cases, most commonly by IGH@-CRLF2 rearrangement or the PAR1 deletion resulting in expression of P2RY8-CRLF2. Both alterations result in increased cell surface expression of CRLF2 by leukemic cells, and flow cytometric analysis of CRLF2 expression may be used to detect CRLF2-rearranged cases (Figure 2e). Less commonly, CRLF2 is rearranged to other, as yet unknown partner genes or harbors presumed activating mutations, most commonly F232C.73, 75 A striking observation is that CRLF2 alteration, most commonly the PAR1 deletion, is present in over 50% of ALL associated with Down's syndrome (DS-ALL),61, 74 in which other chromosomal rearrangements characteristic of childhood ALL are uncommon.76 The basis for this increased frequency in DS-ALL is currently unknown.

In both DS- and non-DS-ALL, CRLF2 rearrangement is significantly associated with the presence of activating JAK mutations.61, 71, 73, 74 Over half of CRLF2-rearranged cases harbor activating JAK1 or JAK2 mutations, and conversely, nearly all JAK-mutated cases have CRLF2 rearrangements, suggesting that these lesions together contribute to leukemogenesis. Importantly, in non-DS-ALL, CRLF2 alteration and JAK mutations are associated with the presence of IKZF1 alterations, and several studies have observed strong associations between CRLF2/JAK alterations and very poor outcome,70, 77 suggesting that JAK inhibition may be a useful therapeutic approach in these high-risk cases that at present frequently fail maximal therapy. Importantly, however, the association between CRLF2 alterations and poor outcome has not been observed in all cohorts,61 and the association with inferior outcome may be in part attributable to cohorts enriched for high-risk ALL cases, or cases of Hispanic/Latino ethnicity, which is associated with CRLF2 rearrangement.70

CRLF2 forms a heterodimeric receptor with interleukin-7 receptor alpha for the cytokine thymic stromal lymphopoietin.78, 79, 80 thymic stromal lymphopoietin/CRLF2 signaling has a role in dendritic cell development,81 T cell responses,82, 83 allergic inflammation,84, 85, 86 and promotes the proliferation of normal and leukemic B cells,87, 88, 89, 90, 91 but at present the requirement for CRLF2 signaling in normal B-lymphoid ontogeny is unclear, and it may be dispensable.88, 92 The downstream mediators of thymic stromal lymphopoietin/CRLF2 signaling are poorly defined and may differ between human and mouse, and activation of JAK–STAT signaling has been described for the human but not CRLF2.92 These differences may, in part, be due to limited homology of both the receptor and ligand across species.

Although the role of CRLF2 in lymphopoiesis is incompletely understood, existing data suggest that aberrant CRLF2/JAK signaling contributes to leukemogenesis. Expression of either CRLF2 or mutant JAK alleles alone in Ba/F3 cells, a murine IL-3-dependent pro-B-cell line widely used to examine the transforming effects of kinase mutations, usually does not result in transformation.61 A notable exception is JAK1 V658F, the homolog of JAK2 V617F, which transforms this cell line irrespective of cytokine receptor coexpression.61 Before the identification of CRLF2 alterations in ALL, JAK mutations in ALL were shown (like the JAK2 V617F mutation observed in myeloproliferative disease) to transform Ba/F3 cells expressing the erythropoietin receptor (Ba/F3-EpoR cells) to cytokine-independent growth and result in constitutive Jak–Stat activation,56, 63, 66 suggesting that interaction of Jak mutants with a cytokine receptor scaffold is required for transformation. Subsequent studies have shown that coexpression of JAK mutations and CRLF2 in Ba/F3 cells is transforming (Figures 2f and g), and that this transformation is inhibited by either pharmacological JAK inhibition or short hairpin RNA-mediated knockdown of CRLF2 expression61, 73, 74 (Figure 2h). Similarly, studies using primary murine hematopoietic progenitors have shown that enforced expression of CRLF2 alone promotes lymphoid expansion, but this is insufficient to result in the development of leukemia71 (and unpublished data). Ongoing studies modeling CRLF2 dysregulation and JAK mutations will be of interest not only to determine the role of these alterations in leukemogenesis, but also to provide preclinical models of ALL that faithfully recapitulate human leukemia in which to test the efficacy of pharmacological JAK inhibitors. This is particularly important as therapeutic JAK inhibition is now being pursued in other JAK-mutated diseases, such as the myeloproliferative diseases.93, 94 Importantly, these studies must also model the effects of additional genetic lesions commonly observed in CRLF2/JAK-mutated ALL, including deletion or mutation of B-lymphoid transcriptional regulators such as IKZF1 and PAX5 and deletion of CDKN2A/CDKN2B (INK4/ARF). It will also be important to determine the potential utility of JAK inhibitors in BCR-ABL1-like and/or CRLF2-rearranged cases that lack JAK mutations but exhibit evidence of JAK–STAT pathway activation by gene expression profiling or flow-cytometric analysis.

Future directions for genomic profiling in high-risk ALL

Integrated analysis of genomic data has been exceptionally informative in identifying novel genetic alterations in ALL; however, our understanding of the genetic basis of high-risk disease remains incomplete. For example, almost one-half of CRLF2-rearranged cases lack an activating JAK mutation, yet may have a BCR-ABL1-like gene expression profile, suggesting that additional cooperating or kinase-activating lesions remain to be identified. Moreover, many ‘BCR-ABL-like’ cases lack CRLF2 alterations, and the genetic alterations driving these leukemias remain unknown. Similarly, there remains a substantial proportion of ALL cases that lack known cytogenetic alterations and fail therapy, and the frequency of these cases rises with increasing age. Compared with childhood leukemia, there is a lack of detailed, high-resolution genomic profiling data from adolescent and adult ALL,95, 96, 97 which has a markedly inferior outcome to that of childhood ALL. The frequency of Ph+ ALL rises progressively with increasing age, but this alone does not account for the poor outcome of ALL with increasing age, and at present it is unclear whether the frequency of poor-risk mutations and expression profiles observed in pediatric ALL will be recapitulated in the adult setting. This is a critical issue and is an area of active enquiry. Furthermore, several high-risk subtypes of leukemia have either not been studied in detail (for example, ALL with low hypodiploidy)98, 99, 100, 101 or have few structural genetic alterations on microarray analysis (for example, MLL-rearranged leukemia).15, 28 In addition, although microarray platforms have provided important insights into DNA copy number alterations in ALL, they do not directly detect structural rearrangements or DNA sequence alterations.

Thus, future genomic profiling studies of ALL require detailed analysis of less well-studied cohorts and the application of novel genomic profiling technologies that interrogate both genetic and epigenetic changes. Detailed candidate gene-sequencing studies in ALL have identified new mutations in B-progenitor ALL,102 suggesting that genome-wide sequencing is required to identify the full complement of genetic alterations in this disease. This is now feasible with next-generation, massively parallel sequencing of tumor nucleic acids.103 Next-generation sequencing of either tumor DNA or RNA has identified new targets of mutation in AML,104, 105 T-lineage ALL106 and lymphoma,107 and has identified new targets of rearrangement in cancer,108, 109 including B-lineage ALL.110 It is likely that as the time and cost requirements of these methods decline, sequencing-based approaches will assume greater importance in interrogating cancer genomes and may supplant array-based methodologies.


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We thank colleagues at St Jude Children's Research Hospital and the Children's Oncology Group who have contributed to this work. The studies described here were supported by ALSAC/St Jude and the National Institutes of Health. CGM is supported by the American Society of Hematology and the American Association of Cancer Research, and is a Pew Scholar in the Biomedical Sciences.

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Correspondence to C G Mullighan.

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Collins-Underwood, J., Mullighan, C. Genomic profiling of high-risk acute lymphoblastic leukemia. Leukemia 24, 1676–1685 (2010).

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  • acute lymphoblastic leukemia
  • relapse
  • CRLF2
  • JAK

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