Acute Leukemias

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia


Loss of p53—a tumor suppressor gene located on the short arm of chromosome 17 (band 17p13.1)—was detected in 105 out of 2272 (5%) adult acute myeloid leukemia (AML) patients who took part in the Study Alliance Leukemia AML96 and AML2003 multi center trials. There were 85 patients with 17p (p53) deletion with multiple aberrations and 20 patients with a 17p (p53) deletion as single aberration or with only one additional chromosomal abnormality. None of the p53-deleted patients displayed additional low-risk aberrations, like t(8;21) or inv(16). Significant positive association between p53 deletion and other high-risk factors was identified for del(5q) (P<0.001), −5 (P<0.001) and −7 (P<0.05). The molecular risk factors FLT3-ITD and NPM1 mutation showed an inverse correlation to the p53 deletion in complex aberrant patients (P<0.001). The multivariate analysis revealed p53 deletion without multiple aberrations as an independent negative prognostic factor for disease-free survival (P<0.001), relapse risk (P=0.028) and overall survival (P<0.001). Thus, the single p53 deletion should be considered as a high-risk aberration for future risk-adapted treatment strategies in AML.


Acute myeloid leukemia (AML) is a genetically heterogeneous disease where clonal chromosomal aberrations can be detected in about 50% of the cases. On the one hand, large studies confirmed the independent prognostic role of cytogenetics for therapy outcome.1, 2, 3, 4, 5, 6 Most of the recurring chromosomal aberrations can be associated with individual prognosis. On the other hand, there are more infrequent aberrations of which the prognosis has not been evaluated so far. For this reason, patients with these aberrations are treated in the intermediate-risk group even though their prognostic value remains undefined. The single p53 deletion by loss of 17p belongs to this unevaluated group.

A deletion of 17p commonly involves the tumor suppressor gene p53 on band 17p13.1 with allelic loss of the gene.7 p53 is a tumor suppressor that induces cell-cycle arrest with following DNA repair or apoptotic cell death in response to genotoxic substances, oncogenes, hypoxia, DNA damage or ribonucleotide depletion.8 Inactivation of p53 plays an important role in neoplastic transformation in solid tumors and it has also been reported in hematological malignancies in association with progression of disease.9, 10, 11, 12 Most often loss of 17p is accompanied by a complex aberrant karyotype, which in principle results in a poor outcome.5, 6, 13, 14, 15, 16 However, in some cases the p53 deletion is present as a single chromosomal aberration and as a consequence treated in the standard risk group. So far, association of p53 mutations with poor overall survival (OS) has been described in AML,17, 18, 19, 20, 21 but the prognostic impact of 17p aberrations in AML has been evaluated only in the context of complex aberrant karyotypes or other unfavorable cytogenetic markers.5, 6, 16 Recently published data of 336 patients with AML including 9 patients with loss of 17p as sole abnormality revealed in vitro drug resistance and short OS in patients with 17p aberrations leading to p53 deletion.22

In this study, we investigated the incidence, prognostic value, biological and clinical features of a p53 deletion in a large series of AML patients with or without complex aberrant karyotypes.

Patients and methods


Between February 1996 and August 2007, cytogenetic analyses were performed on 2272 AML patients who took part in the AML96 and AML2003 trial of the Study Alliance Leukemia (SAL). A list of the participating study centers and physicians is given in the Acknowledgement. Patients diagnosed with the subtype AML FAB M3 and M3v were excluded and treated separately in European APL protocols. The studies were approved by the ethics committees of the University of Dresden and by those of all other participating centers of the study group. The protocols are in agreement with the Helsinki declaration and registered with the NCT numbers 00180115 (AML96) and 00180102 (AML2003). Written informed consent was obtained from each patient before inclusion.

Risk stratification

Patients 60 years of age were allocated to three risk groups classified after standard cytogenetic analysis. In the AML96 trial the following risk groups were defined: low risk—t(8;21) with or without additional aberrations; intermediate risk—normal karyotype, inv(16) with or without additional aberrations, other aberrations excluded from low or high risk; high risk—−5/del(5q), −7/del(7q), hypodiploid karyotype (except 45,X,−X or −Y), inv(3q), abnormal 12p, abnormal 11q, +11, +13, +21, +22, t(6;9), t(9;22), t(3;3), complex aberrations (3 independent chromosome aberrations), therapy-related AML. In the AML2003 study the risk groups were classified as follows: low risk—t(8;21) or inv(16)/t(16;16) with or without additional aberrations; intermediate risk—normal karyotype, other aberrations excluded from low or high risk; high risk—−5, del(5q), −7, inv(3q), t(3;3), t(6;9), t(6;11), t(11;19), +8 as single aberration or with one additional aberration (except t(9;11)), multiple aberrations (3 independent aberrations), blasts >10% on day 15 after the first induction therapy, FLT3 ratio >0.8 (mutated allele to wild-type allele).

No risk stratification was applied to patients older than 60 years of age.


Patients were treated risk adapted according to the AML96 protocol which has been published previously23 and to the AML2003 treatment scheme.

In the AML2003 trial only patients 60 years of age were included. They were randomized into four arms with two arms receiving a risk-adapted intensified therapy and two arms receiving a standard therapy. The induction therapy was equal for all patients consisting of two courses of DA (daunorubicine 60 mg/m2 days 3–5; ara-C 100 mg/m2 days 1–7). High-risk patients of the intensified therapy arms received an early related or unrelated allogeneic hematopoietic stem cell transplant (HSCT) in aplastic phase after induction therapy. The postremission chemotherapy was either a consolidation with three cycles of ara-C (2 × 3 g/m2 days 1, 3, 5) or two cycles of MAC (ara-C 2 × 1 g/m2 days 1–6; mitoxantrone 10 mg/m2 days 4–6) and one cycle of MAMAC (ara-C 2 × 1 g/m2 days 1–5; m-AMSA 100 mg/m2 days 1–5). In the standard arms patients with an HLA-identical related donor received an allogeneic HSCT. If no HLA-identical donor could be identified, high-risk or intermediate-risk patients within the intensified treatment arms were assigned to an autologous HSCT as second consolidation.

Complete remission (CR) was defined as the presence of less than 5% blast cells in a standardized bone marrow (BM) aspirate after second course of induction therapy and a fully regenerated peripheral blood count according to the previously published consensus criteria.24

Cytogenetic analysis

BM or peripheral blood samples were obtained at the stage of diagnosis. Conventional cytogenetic analyses were performed on short-term cultured BM and peripheral blood cells (24, 48 h). GTG-banding technique was done according to routine cytogenetic procedures. Clonal abnormalities were described in accordance to the International System of Human Cytogenetic Nomenclature (ISCN 2005).25 A complex aberrant karyotype was defined as the presence of three or more independent aberrations. Deletion of p53 (band 17p13.1) was implicated due to the following cytogenetical alterations: −17, isochromosome i(17)(q10), deletion del(17)(pvar(variable)), unbalanced translocations der(var)t(var;17)(var;qvar),−17 or der(var)t(var;17)(var;pvar),−17 or der(17)t(17;var)(pvar;var), balanced translocation t(12;17)(p11;p13) (n=1 patient, interphase FISH with 76% p53 deletion); additive material: add(17)(pvar), dicentric chromosome dic(var;17)(var;pvar), ring chromosome r(17)(pvarqvar).

Additionally, in cases of chromosome 17 alterations in cytogenetics, we performed fluorescence in situ hybridization (FISH) to confirm or exclude a p53 deletion. Some investigations were retrospective, thus, usable material for FISH analyses was only available in 98 out of 105 patients. Three out of these seven patients had a single 17p deletion, however, karyotype description was informative (isochromosome i(17)(q10), derivative chromosome der(17)t(11;17)(q14;p12)). In the complex aberrant group also there were four patients without available material but complete karyotype analyses leaving no doubt concerning 17p13 deletion (r(17)(p11q21), i(17)(q10), −17, dic(5;17)(q11;p11)). Patients with unclear state of p53 (that is, incomplete metaphases, balanced translocations, marker chromosomes) but without any available material were excluded from the study (n=3).

Fluorescence in situ hybridization

For the evaluation of the p53 status we used freshly prepared slides from methanol/acetic acid fixed cells or frozen BM and peripheral blood (blasts >15%) smears, respectively. The following DNA probes, Fa. Abbott (Wiesbaden-Delkenheim, Germany), were used: LSI p53 (Spectrum Orange) and CEP 17 (Spectrum Green) as reference locus. Hybridizations were performed as recommended by the manufacturer with the following modifications: chromosome and probe denaturation were done at 76 °C for 6 min and at 76 °C for 5 min, respectively. Fluorescence signals were visualized with the fluorescence microscope Eclipse (Fa. NIKON, Germany) on interphase nuclei. For each sample, 200 cells were counted by two independent observers and the percentage of aberrant cells was averaged. A cut-off level of 13% was determined in a set of normal control samples.

Statistical methods

All statistical analyses were performed using the SPSS software package, version 15.0 (Chicago, IL, USA). To analyze the influence of p53 deletion on the outcome, we divided patients into four groups: normal karyotype (standard group, A), p53 deletion as single aberration or at most with one additional chromosomal abnormality (in the following termed as ‘single p53 deletion’, B), complex aberrant karyotype without p53 deletion (C) and complex aberrant karyotype with p53 deletion (D). Clinical parameters and outcome of each aberrant group were compared to the standard group.

Correlations of parametric clinical variables across groups were analyzed using two-sided Fisher's exact test whereas nonparametric variables were compared by using the Mann–Whitney U-test. Multivariate analyses of the correlation between clinical parameters and the therapy response were performed by stepwise logistic regression. Multivariate analyses of the correlation between clinical variables and survival were carried out by Cox regression.

OS and disease-free survival (DFS) analyses were performed using the Kaplan–Meier method and survival curves were compared using the log-rank test. DFS was defined as the time from CR to relapse or death. OS was defined as period from diagnosis to death.

P values less than 0.05 were considered to be significant.


Frequency of p53 deletion

Depending on the karyotype and the state of p53 all 2272 patients were separated into six distinct categories (Table 1). A total of 105 out of 2272 patients (5%) had a p53 deletion, whereas most of these cases had a complex aberrant karyotype (85 out of 105 patients). In this distinct group, the frequency of the p53 loss was 29% (85 out of 291 patients). Only 20 patients (1%) presented a single p53 deletion. In patients >60 years of age the incidence of this distinct group was 1.4%.

Table 1 Karyotype groups

Clinical and hematological characterization of patients with p53 deletion

A survey of the biological and clinical features of the patients is given in Table 2. The characteristics of the normal karyotype patients (group A, n=1144), who made up the standard group, were compared with the following groups: patients with a p53 deletion as single aberration or with one additional abnormality (single p53 deletion, group B, n=20), complex aberrant patients without a p53 deletion (group C, n=206), complex aberrant patients with p53 deletion (group D, n=85). The patients of group D (complex aberrant with p53 deletion) showed in comparison with the standard group A a very low white blood cell count (WBC, 4 vs 18 Gpt/l, P<0.001), lower BM blasts (44 vs 64%, P<0.001), higher percentage of CD34+ cells (37 vs 11%, P<0.001) and a more frequent presence of therapy-related AML (t-AML, 12 vs 2%, P<0.001). No significant differences could be determined for the characteristics of the small subgroup of patients with p53 deletion as single aberration (group B) in comparison with the normal karyotype group A, except for a higher CD34 expression (40 vs 11%, P=0.034). However, the option to do precise statistics for group B was restricted because of the small number of cases, which was due to the rarity of that cytogenetic entity. Keeping in mind that the groups C/D are the complex aberrant groups, it was interesting to look for biological differences. However, except for BM blasts (C: 60% vs D: 44%; P<0.001) there were no significant differences.

Table 2 Clinical and hematological features of patients with or without p53 deletiona

Cytogenetic characterization of p53 deletion

One patient in the group of single p53 deletion (group B) presented a failure of conventional karyotyping. The extensive interphase analyses revealed only a monosomy 7 and loss of p53.

Interestingly, 13 out of 19 (68%) patients with single p53 deletion presented an isochromosome i(17)(q10) whereas only 10% of the complex aberrant patients had an i(17)(q10) (P<0.001). In the complex aberrant cases the loss of p53 resulted mostly from monosomy 17 (48%, P<0.001) and unbalanced translocations (28%, n.s. (not significant)). Other aberrations like additional material (n=7), deletions of 17p (n=4), dicentric chromosomes (n=3), ring chromosomes (n=1) and balanced translocations (n=1) were infrequent events.

Correlation of p53 deletion with other cytogenetic and molecular risk factors

To evaluate the association of p53 deletion with specific cytogenetic risk factors, all aberrant patients were divided into two subgroups with the criteria—presence (n=105) or absence (n=1023) of p53 deletion. Interestingly, none of the p53-deleted patients showed the low-risk aberrations t(8;21) or inv(16)/t(16;16) (t(8;21): 0 vs 10%, P<0.001; inv(16)/t(16;16): 0 vs 13%, P<0.001). Significant positive association of p53 deletion with established high-risk aberrations was identified for del(5q) (40 vs 10%, P<0.001), −5 (8 vs 0.5%, P<0.001) and −7 (17 vs 9%, P<0.05) whereas inv(3q)/t(3;3), t(6;9), abn(11q23) were not observed in combination with a p53 deletion. Trisomy 8 was seen with the same frequency in both subgroups (19%).

Furthermore, we have seen an inverse correlation between p53 deletion and the molecular risk factors FLT3-ITD (internal tandem duplication of FLT3 gene (fms-like tyrosine kinase 3); 0 vs 33%, P<0.001) and NPM1 (mutation of nucleophosmin gene; 2 vs 49%, P<0.001) in complex aberrant patients, compared to patients with normal karyotypes. No statistical difference was found for the parameter MLL-PTD (partial tandem duplication of MLL gene (mixed-lineage/myeloid lymphoid leukemia)). Among the subgroup with single p53 deletion only one case with FLT3-ITD mutation was observed.

Prognostic impact of p53 deletion

Table 3 shows the probability of DFS and OS for the four different karyotype groups (groups A–D). The mean observation time was 30 months (range 0–113). In the univariate analysis, the presence of p53 deletion was correlated with clinical outcome. As shown in Figure 1, DFS (1a) and OS (1b) was impaired for all of the three aberrant subgroups compared to normal karyotype (P<0.001). Moreover, all patients with p53 deletion showed significantly poorer 2y-DFS (B: P=0.008; D: P=0.042) as well as shorter 2y-OS (B: n.s.; D: P=0.033) compared to complex aberrant patients without p53 deletion. The response to induction therapy was decreased in patients with a complex aberrant karyotype (P<0.001) independent of the presence of a p53 deletion compared to patients with normal karyotype.

Table 3 Treatment outcome
Figure 1

Kaplan–Meier analysis for probability of survival according to different karyotypes. Comparison of (a) 2-year disease-free survival (DFS; n=742) and (b) 2-year overall survival (OS; n=1449) in all patients with karyotype: normal, not complex with del(p53), complex without del(p53), complex with del(p53). Survival curves were compared using log-rank test. CI, confidence interval.

Multivariate analyses were performed to investigate whether a single p53 deletion represents an independent prognostic factor and moreover, to evaluate whether p53 deletion influences the outcome of complex aberrant patients. Several known risk factors were included in the model (age, WBC, platelet count, BM blasts, CD34 expression, secondary AML, molecular risk factors: FLT3-ITD, NPM1, MLL-PTD; cytogenetic risk factors: −5/5q−, −7). Regarding the complex aberrant patients, the p53 deletion showed an independent negative prognostic value for DFS (P=0.031), relapse (P=0.003) and OS (P=0.046). Patients’ age (P<0.001), platelet count (P=0.009), a preceding myelodysplastic syndrome (P=0.023) and −5/5q− (P=0.032) independently influenced achieving of a CR. Furthermore, WBC ((DFS: n.s., relapse: P=0.043), BM blasts (DFS: P=0.007; relapse: 0.003) and age (DFS: n.s., relapse: P=0.039) were negative factors for DFS and relapse. Age (P<0.001), WBC (P=0.001), platelet count (P=0.002), t-AML (P=0.012) and –5/5q− (P=0.022) were predictive for OS.

Regarding all subgroups, the multivariate analysis (Table 4) revealed p53 deletion without multiple aberrations as an independent negative prognostic factor for DFS (P<0.001), relapse (P=0.028) and OS (P<0.001), but not for therapy response (CR). In detail, 45% of patients in this group achieved CR, the median DFS time was 4 months, and the median OS time was 5 months. 2y-DFS and 2y-OS were 0% (Table 3).

Table 4 Prognostic factors for CR, DFS, relapse, OS. Multivariate analysis

Furthermore, the multivariate analysis showed that CD34 expression (P<0.001), complex aberrant karyotype without p53 deletion (P<0.001) and a preceding myelodysplastic syndrome (P<0.001) were the most important prognostic factors for therapy failure, whereas age (P<0.001), WBC (P<0.001), CD34 expression (P<0.001), complex aberrations (P<0.001) and a single p53 deletion (P<0.001) were strong prognostic factors for poor OS (Table 4).


During the last two decades the evaluation of the prognostic impact of many clinical and genetic features has established the basis for risk-adapted treatment approaches in patients with AML. Cytogenetic findings at diagnosis have been approved as the most important predictive factors for treatment outcome. Based on that, patients can be divided into three main risk groups: favorable, intermediate and adverse. This is valid for the frequent recurring chromosomal aberrations where the prognostic impact is well documented. Up to now, for seldom aberrations like a single p53 (17p) deletion, the knowledge is unsatisfying. Published data of the CALGB 8461 trial5 documented monosomy 17 or loss of 17p as a single abnormality with a frequency of two out of 1213 patients. Most often the loss of 17p/−17 is accompanied by a complex aberrant karyotype with a poor outcome.5, 6, 13, 14, 15, 16

In our study of patients with AML, the incidence of p53 deletions was 5% (105 out of 2272) which is consistent with the observations of other groups.5, 26 There were only 20 patients (1%) with single p53 deletion, proving that this is a rare but recurring cytogenetic entity. Most of the patients had a complex aberrant karyotype (85 out of 105 patients).

Our results prove clearly that it is not advisable to classify patients with a single p53 deletion or with only one additional aberration (group B) into the intermediate risk group. Median OS was only 5 months for this group of patients. In the multivariate analysis a single p53 deletion is a strong independent negative prognostic factor for DFS and OS. This is in line with the observed poor outcome of patients with p53 mutations17, 18, 20, 21 and with the recently published data of patients with 17p aberrations.22

The subgroups with p53 deletion showed distinct biological characteristics. Independent of the state of complexity, there were significant higher amounts of CD34+ cells. Published in vitro investigations27, 28 indicated that the loss of p53 function could cause cell-cycle arrest in a very primitive stage of maturation. Thus, the cell is not able to differentiate anymore. Due to an inability of apoptosis proproliferative signals result in an uninhibited growth of aberrant CD34+ progenitor cells.

None of the p53-deleted patients had additional low-risk aberrations, like t(8;21) or inv(16)/t(16:16), whereas a significant positive association between p53 deletion and established high-risk aberrations (del(5q), −5, −7) was observed, which is in line with other reports.14, 21, 29, 30 Furthermore, we could see an inverse correlation between p53 deletion and the molecular risk factors FLT3-ITD and NPM1 mutation.

The specific cytogenetic types of the p53 deletion varied in the subgroups. Of 20 patients with single p53 deletion, 13 presented an isochromosome i(17)(q10), resulting in a hemizygous deletion of p53. Recently, this aberration has been characterized and the locus 17p11.2 was identified as the breakpoint cluster region resulting in a dicentric isochromosome. However, no associated p53 mutation of the remaining allele was found in hematological malignancies.31 In contrast, in the complex aberrant group p53 deletion was predominantly caused by monosomy 17 and unbalanced translocations. This supports the presumption of Schoch et al.14 that the loss of genetic material is more common than the gain in AML with complex aberrant karyotype.

The loss of 17p in AML is often accompanied by a p53 mutation resulting in a loss of heterozygosity.7, 13, 15, 19, 32, 33 Conversely, p53 mutations without cytogenetical alteration are a rare event.32, 33 In contrast, 10–30% of patients have a cytogenetical p53 deletion with wild-type configuration of the remaining allele.7, 13, 33 Data from experiments on mice reveal that the loss of one p53 allele could be sufficient for tumorigenesis.34 This could be relevant for the development of leukemia in patients with single p53 deletion. Another possibility is the inactivation of downstream mediators of p53, which affect not only the cell-cycle arrest, but also the repair of DNA and the apoptosis. Alternatively, overexpression of genes inhibiting p53 and promoting degradation of p53 can be considered, for instance MDM2 gene amplifications have been detected in B-CLL.35

Moreover, an interesting investigation of Sankar et al.36 revealed only 3 out of 17 patients presenting a p53 inactivation in FISH, in contrast to 14 patients with locus 17p13.3 deleted. Thus, other tumor suppressor genes on the short arm of chromosome 17 may be involved in the development of leukemia.

In view of complex aberrant patients our data revealed p53 deletion as an independent negative prognostic factor for DFS, relapse risk and OS. The response to induction therapy was poor in both complex aberrant subgroups indicating that the resistance to cytotoxic substances must be caused by other mechanisms. Recently published data of multi-drug-resistance gene expression showed negative influence on therapy response in complex aberrant patients.37 Association of p53 deletion and MDR1 expression has been confirmed for CML, but not for AML.38 An independent negative additive effect with decreased induction of apoptosis and increased cytostatica efflux can therefore be considered. Interestingly, Nahi et al.22 have recently shown a greater resistance to different conventional antileukemic drugs in p53-deleted cells, except for daunorubicine and ara-C which were used in the AML2003 trial as induction therapy.

In conclusion, patients with a single p53 deletion have shown a worse treatment outcome than patients with normal karyotype and should be therefore classified into the high-risk category as the complex aberrant patients have already been. Due to the poor outcome, it is necessary to provide another therapy strategy to patients with p53 deletion than conventional treatment strategies including allogeneic stem cell transplantation. An alternative therapeutic option is offered through the development of substances influencing the function of p53 in a specific way. In this regard, interesting results about the substance PRIMA-1 (p53-dependent reactivation and induction of massive apoptosis) were published recently.39 Furthermore, the latest results of research showed improvement in the in vitro drug chemosensitivity in p53-deleted cells after coincubation of RITA (reactivation of p53 and induction of tumor cell apoptosis) and PRIMA-1.40


  1. 1

    Fenaux P, Preudhomme C, Lai JL, Morel P, Beuscart R, Bauters F . Cytogenetics and their prognostic value in de novo acute myeloid leukaemia: a report on 283 cases. Br J Haematol 1989; 73: 61–67.

  2. 2

    Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

  3. 3

    Mrozek K, Heinonen K, Bloomfield CD . Prognostic value of cytogenetic findings in adults with acute myeloid leukemia. Int J Hematol 2000; 72: 261–271.

  4. 4

    Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001; 98: 1312–1320.

  5. 5

    Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325–4336.

  6. 6

    Haferlach T, Kern W, Schoch C, Schnittger S, Sauerland MC, Heinecke A et al. A new prognostic score for patients with acute myeloid leukemia based on cytogenetics and early blast clearance in trials of the German AML Cooperative Group. Haematologica 2004; 89: 408–418.

  7. 7

    Soenen V, Preudhomme C, Roumier C, Daudignon A, Lai JL, Fenaux P . 17p Deletion in acute myeloid leukemia and myelodysplastic syndrome. Analysis of breakpoints and deleted segments by fluorescence in situ. Blood 1998; 91: 1008–1015.

  8. 8

    Vousden KH, Lu X . Live or let die: the cell's response to p53. Nat Rev Cancer 2002; 2: 594–604.

  9. 9

    Sander CA, Yano T, Clark HM, Harris C, Longo DL, Jaffe ES et al. p53 mutation is associated with progression in follicular lymphomas. Blood 1993; 82: 1994–2004.

  10. 10

    Nakai H, Misawa S, Taniwaki M, Horiike S, Takashima T, Seriu T et al. Prognostic significance of loss of a chromosome 17p and p53 gene mutations in blast crisis of chronic myelogenous leukaemia. Br J Haematol 1994; 87: 425–427.

  11. 11

    Dohner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–1589.

  12. 12

    Fenaux P, Preudhomme C, Lai JL, Quiquandon I, Jonveaux P, Vanrumbeke M et al. Mutations of the p53 gene in B-cell chronic lymphocytic leukemia: a report on 39 cases with cytogenetic analysis. Leukemia 1992; 6: 246–250.

  13. 13

    Haferlach C, Dicker F, Herholz H, Schnittger S, Kern W, Haferlach T . Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia 2008; 22: 1539–1541.

  14. 14

    Schoch C, Haferlach T, Bursch S, Gerstner D, Schnittger S, Dugas M et al. Loss of genetic material is more common than gain in acute myeloid leukemia with complex aberrant karyotype: a detailed analysis of 125 cases using conventional chromosome analysis and fluorescence in situ hybridization including 24-color FISH. Genes Chromosomes Cancer 2002; 35: 20–29.

  15. 15

    Schoch C, Kern W, Kohlmann A, Hiddemann W, Schnittger S, Haferlach T . Acute myeloid leukemia with a complex aberrant karyotype is a distinct biological entity characterized by genomic imbalances and a specific gene expression profile. Genes Chromosomes Cancer 2005; 43: 227–238.

  16. 16

    van der Holt B, Breems DA, Berna Beverloo H, van den Berg E, Burnett AK, Sonneveld P et al. Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value: results from a prospective clinical trial. Br J Haematol 2007; 136: 96–105.

  17. 17

    Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 1994; 84: 3148–3157.

  18. 18

    Nakano Y, Naoe T, Kiyoi H, Kitamura K, Minami S, Miyawaki S et al. Prognostic value of p53 gene mutations and the product expression in de novo acute myeloid leukemia. Eur J Haematol 2000; 65: 23–31.

  19. 19

    Kurosawa M, Okabe M, Kunieda Y, Asaka M . Analysis of the p53 gene mutations in acute myelogenous leukemia: the p53 gene mutations associated with a deletion of chromosome 17. Ann Hematol 1995; 71: 83–87.

  20. 20

    Melo MB, Ahmad NN, Lima CS, Pagnano KB, Bordin S, Lorand-Metze I et al. Mutations in the p53 gene in acute myeloid leukemia patients correlate with poor prognosis. Hematology 2002; 7: 13–19.

  21. 21

    Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol 2001; 19: 1405–1413.

  22. 22

    Nahi H, Lehmann S, Bengtzen S, Jansson M, Mollgard L, Paul C et al. Chromosomal aberrations in 17p predict in vitro drug resistance and short overall survival in acute myeloid leukemia. Leuk Lymphoma 2008; 49: 508–516.

  23. 23

    Schaich M, Ritter M, Illmer T, Lisske P, Thiede C, Schakel U et al. Mutations in ras proto-oncogenes are associated with lower mdr1 gene expression in adult acute myeloid leukaemia. Br J Haematol 2001; 112: 300–307.

  24. 24

    Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

  25. 25

    Shaffer LG, Tommerup N (eds). ISCN (2005): An International System for Human Cytogenetic Nomenclature. S Karger: Basel, Switzerland, 2005.

  26. 26

    Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075–4083.

  27. 27

    Kastan MB, Radin AI, Kuerbitz SJ, Onyekwere O, Wolkow CA, Civin CI et al. Levels of p53 protein increase with maturation in human hematopoietic cells. Cancer Res 1991; 51: 4279–4286.

  28. 28

    Takeda K, Minowada J, Bloch A . Kinetics of appearance of differentiation-associated characteristics in ML-1, a line of human myeloblastic leukemia cells, after treatment with 12-O-tetradecanoylphorbol-13-acetate, dimethyl sulfoxide or 1-beta-D-arabinofuranosylcytosine. Cancer Res 1982; 42: 5152–5158.

  29. 29

    Castro PD, Liang JC, Nagarajan L . Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms. Blood 2000; 95: 2138–2143.

  30. 30

    Horiike S, Misawa S, Kaneko H, Sasai Y, Kobayashi M, Fujii H et al. Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype. Leukemia 1999; 13: 1235–1242.

  31. 31

    Fioretos T, Strombeck B, Sandberg T, Johansson B, Billstrom R, Borg A et al. Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations. Blood 1999; 94: 225–232.

  32. 32

    Fenaux P, Jonveaux P, Quiquandon I, Lai JL, Pignon JM, Loucheux-Lefebvre MH et al. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood 1991; 78: 1652–1657.

  33. 33

    Lai JL, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke M, Lepelley P et al. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations. Leukemia 1995; 9: 370–381.

  34. 34

    Venkatachalam S, Shi YP, Jones SN, Vogel H, Bradley A, Pinkel D et al. Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J 1998; 17: 4657–4667.

  35. 35

    Watanabe T, Hotta T, Ichikawa A, Kinoshita T, Nagai H, Uchida T et al. The MDM2 oncogene overexpression in chronic lymphocytic leukemia and low-grade lymphoma of B-cell origin. Blood 1994; 84: 3158–3165.

  36. 36

    Sankar M, Tanaka K, Kumaravel TS, Arif M, Shintani T, Yagi S et al. Identification of a commonly deleted region at 17p13.3 in leukemia and lymphoma associated with 17p abnormality. Leukemia 1998; 12: 510–516.

  37. 37

    Schaich M, Soucek S, Thiede C, Ehninger G, Illmer T . MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 2005; 128: 324–332.

  38. 38

    Cavalcanti Jr GB, da Cunha Vasconcelos F, Pinto de Faria G, Scheiner MA, de Almeida Dobbin J, Klumb CE et al. Coexpression of p53 protein and MDR functional phenotype in leukemias: the predominant association in chronic myeloid leukemia. Cytometry B Clin Cytom 2004; 61: 1–8.

  39. 39

    Nahi H, Merup M, Lehmann S, Bengtzen S, Mollgard L, Selivanova G et al. PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion. Br J Haematol 2006; 132: 230–236.

  40. 40

    Nahi H, Selivanova G, Lehmann S, Mollgard L, Bengtzen S, Concha H et al. Mutated and non-mutated TP53 as targets in the treatment of leukaemia. Br J Haematol 2008; 141: 445–453.

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We thank the following physicians and participating centers of the SAL study group who entered their patients into the trials: W Siegert, O Rick (Universitätsklinikum Charité Mitte, Berlin); E Thiel (Universitätsklinikum Benjamin Franklin, Berlin); E Späth-Schwalbe, S Hesse-Amojo (Vivantes Klinikum Spandau, Berlin); R Kolloch, U Krümpelmann (Krankenanstalten Gilead, Bielefeld); M Görner, S Probst (Klinikum Mitte, Bielefeld); K-H Pflüger, T Wolff (Ev. Diakonie-Krankenhaus, Bremen); H Heidtmann, L Kalcki (St Joseph Hospital, Bremerhaven); J Hotz, F Marquard (Allgemeines Krankenhaus Celle, Celle); M Hänel, R Herbst (Krankenhaus Küchwald, Chemnitz); G Ehninger, M Schaich (Universitätsklinikum, Dresden); M Grammatzki, G Helm (Universitätsklinikum, Erlangen); JG Saal (Malteser Krankenhaus, Flensburg); H-G Höffkes, M Arland (Klinikum Fulda, Fulda); E Fasshauer, B Opitz (Krankenhaus St Elisabeth und St Barbara, Halle); R Kuse, N Schmitz, R Stuhlmann (Allg. Krankenhaus St Georg, Hamburg); H Schmidt, K Buhrmann (Kreiskrankenhaus, Hameln); H Dürk, B Bechtel (St Marien-Hospital, Hamm); R Teschke, M Burk (Klinikum Stadt, Hanau); A Ho (Universitätsklinikum, Heidelberg); U Kaiser, A Bartholomäus (St Bernward Krankenhaus, Hildesheim); AA Fauser, S Zimber (Klinik für Knochenmarktransplantation und Hämatologie/Onkologie, Idar-Oberstein); H Link, F-G Hagmann (Westpfalz-Klinikum, Kaiserslautern); L Mantovani (Städtisches Klinikum St Georg, Leipzig); K-P Schalk (St Vincent Krankenhaus, Limburg/Lahn); S Fetscher (Sana Kliniken Lübeck, Lübeck); T Wagner (Universitätsklinikum Lübeck, Lübeck); A Neubauer (Universitätsklinikum, Marburg); H Bodenstein, J Tischler (Klinikum Minden, Minden); R Hartenstein, N Brack, H Pohlmann (Krankenhaus München-Harlaching, München); W Wilhelm, H Wandt, K Schäfer-Eckardt (Klinikum Nord, Nürnberg); H Dancygier, B Seeber (Klinikum Offenbach, Offenbach am Main); F Hirsch, I Dressel (Klinikum Offenburg, Offenburg); H Heißmeyer, T Geer (Diakonie-Krankenhaus, Schwäbisch-Hall); E Jähde, J Labenz (Ev. Jung-Stilling Krankenhaus, Siegen); W Aulitzky, L Leimer (Robert-Bosch-Krankenhaus, Stuttgart); E Heidemann, J Kaesberger (Diakonissenkrankenhaus, Stuttgart); MR Clemens, R Mahlberg (Krankenanstalt Mutterhaus der Borromäerinnen, Trier); R Schwerdtfeger (Deutsche Klinik für Diagnostik, Wiesbaden); R Engberding, R Winter (Stadtkrankenhaus Wolfsburg, Wolfsburg); K Wilms, H Rücke-Lanz, F Weissinger (Universitätsklinikum, Würzburg); M Sandmann, A Hellmann (Kliniken St Antonius, Wuppertal).

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Seifert, H., Mohr, B., Thiede, C. et al. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. Leukemia 23, 656–663 (2009) doi:10.1038/leu.2008.375

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  • acute myeloid leukemia
  • p53 deletion
  • loss of 17p
  • outcome
  • prognosis

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