ALL

Genetic heterogeneity of BCR/ABL+ adult B-cell precursor acute lymphoblastic leukemia: impact on the clinical, biological and immunophenotypical disease characteristics

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Abstract

Philadelphia-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (BCP–ALL) is a genetically heterogeneous disease with a very poor prognosis. In this study, we analyzed the frequency of supernumerary Ph, trisomy 8, monosomy 7, and del(9p21) by FISH and its relationship with the characteristics of the disease, in 46 BCR/ABL+ adult BCP–ALL patients. The frequency of supernumerary Ph, trisomy 8, monosomy 7 and del(9p21) was 30%, 20%, 15%, and 24%, respectively. Although all patients displayed a BII/common phenotype, supernumerary Ph and trisomy 8 were associated with higher expression of CD19 and CD22 and of CD19, CD34, CD45, and HLA-DR, respectively; in turn, cases with monosomy 7 showed lower CD19, CD22, CD34, and cCD79a and del(9p21)+ blasts were CD13 and CD33. Overall, similar clinical and hematological features were observed at presentation, independently of the underlying genetic abnormalities. However, relapse-free survival (RFS) was significantly shorter in cases with supernumerary Ph, trisomy 8, and del(9p21), the latter being the most powerful independent prognostic factor for RFS.

Introduction

The Philadelphia (Ph) chromosome defines a subgroup of around one-third of all adults with B-cell precursor acute lymphoblastic leukemia (BCP–ALL) with a very poor prognosis.1, 2, 3 Typically, the Ph chromosome reflects the reciprocal translocation between the long arms of chromosomes 9 and 22 – t(9;22) (q34;q11.2) – and involves the ABL and BCR genes. BCR/ABL+ BCP–ALL have been shown to be cytogenetically heterogeneous. Accordingly, hyperdiploidy with >50 chromosomes and other chromosome gains, including supernumerary Ph and trisomy 8, and chromosome losses (eg monosomy 7 and 9p) have been reported in a variable proportion of BCR/ABL+ BCP–ALL using conventional cytogenetic techniques.3, 4, 5, 6, 7, 8, 9, 10 However, in vitro culture of ALL cells fails to produce adequate metaphases in between 20 and 30% of the patients,3, 4, 5, 6, 7, 8, 9, 10 and conventional cytogenetics frequently fail to detect restricted interstitial chromosome deletions such as those involving the cyclin-dependent kinase inhibitors (CDKI), p16INK4a/p15INK4b/p14ARF located at 9p21.11, 12, 13 Owing to this, more recent studies have systematically used interphase fluorescence in situ hybridization (iFISH) and/or molecular techniques for the detection of these cytogenetics abnormalities.14 Such genetic heterogeneity of BCR/ABL+ BCP–ALL patients may translate into different cell phenotypes, and distinct clinical behavior. In line with this hypothesis, BCR/ABL+ adult BCP–ALL have been reported to be both phenotypically and clinically heterogeneous.3, 4, 5, 6, 7, 8 Gleissner et al3 have reported similar clinical features for mBCR+ and MBCR+ BCP–ALL patients at presentation, cases with p210 mRNA transcripts showing a slightly worse clinical outcome. In turn, Rieder et al4 have found an adverse prognostic impact for monosomy 7 and 9p abnormalities in a group of 66 BCR/ABL+ BCP–ALL patients. In addition, supernumerary Ph has been related to a higher incidence of relapses.5, 6 Despite this, to the best of our knowledge, no study has been reported so far in which the clinical and biological impacts of supernumerary Ph, monosomy 7, trisomy 8 and del(9p21) have been simultaneously explored in t(9;22)+ BCP–ALL patients.

In the present study, we have simultaneously analyzed the frequency of supernumerary Ph, trisomy 8, monosomy 7, and del(9p21) by iFISH in a group of 46 BCR/ABL+ BCP–ALL, and have correlated the results with both the phenotype of leukemic cells and the clinical, biological, and prognostic disease characteristics.

Materials and methods

Patients

A total of 46 adult ‘de novo’ BCR/ABL+ BCP–ALL patients were included in the present study. All patients were diagnosed with Ph+ BCP–ALL based on conventional cytogenetics and molecular analyses in combination with morphological and immunophenotypic data between June 1998 and July 2004. Patients were treated according to the Spanish ALL PETHEMA Cooperative group protocols.15 Complete remission (CR) was defined as <5% blast cells in a regenerated bone marrow (BM) aspirate, in the absence of extramedullary leukemia and with peripheral blood (PB) counts of >1.5 × 109neutrophils/l and >100 × 109platelets/l. By the end of the study, 37 patients had died. Median follow-up was 9 months for the whole series and 7 months for those patients who died and 18 months for those who remained alive.

Conventional karyotyping

In all cases, heparin-anticoagulated fresh BM aspirate samples were obtained at diagnosis and cultured for 24 and 48 h following standard procedures.16 Chromosomes were stained by Giemsa (G-banding) and the karyotypes described according to the ISCN recommendations.17

iFISH studies

iFISH analysis of the t(9;22) translocation was performed at diagnosis using the LSI-bcr/abl dual color (ES) probe (Vysis Inc., Downers Grove, IL, USA), which allows distinction between MBCR/ABL+ and mBCR/ABL+ gene rearrangements.14 Additional iFISH analyses were also performed at diagnosis with centromeric probes specific for chromosomes 7 and 8 labelled with Spectrum Orange (Vysis Inc.) and the LSI p16/CEP9 dual color probe (Vysis, Inc.) as described previously.14, 18 Freshly obtained samples either directly or after being cultured in vitro and prepared according to conventional cytogenetic procedures were used.

For all slides analyzed, a minimum of 200 cells/sample were counted for each probe and only those spots with a similar size, intensity, and shape were counted. Abnormalities of chromosomes 7, 8, and 9 were considered to be present when the proportion of cells showing abnormal spot counts was at a percentage higher than the mean value +2SD of the percentage obtained with the same probe in 10 control BM samples; values for monosomy 7, trisomy 8, and del(9p21) were of >3%, >2%, and >5%, respectively. The percentage of abnormal cells showing these alterations was 62±23, 46±28, and 63±28%, respectively.

Immunophenotypic analyses

Immunophenotypic studies were performed in all cases at the moment of diagnosis on erythrocyte-lysed whole BM samples using multicolor direct immunofluorescence techniques analyzed on a FACSCalibur flow cytometer (Becton/Dickinson Biosciences (BDB), San Jose, CA, USA), as described previously in detail.19 The following fluorochrome-conjugated monoclonal antibodies (MAb) were tested: (1) fluorescein isothiocyanate (FITC)-conjugated anti-CD4, CD5, CD7, CD10 CD15, CD19, CD34, CD61, CD65, nuclear-TDT, cytoplasmatic (c)MPO; (2) phycoerythrin (PE)-conjugated anti-CD2, CD5, CD8, CD10, CD13, CD14, CD20, CD22, CD33, CD34, CD38, CD56, CD117, 7.1, CD11b, cCD79a, cIgμ, and (3) peridin chlorophyll protein (PerCP)-conjugated anti-CD19, CD20, CD45, HLA-DR. All Mab reagents directly conjugated with fluorochromes were purchased from BDB except anti-CD10-FITC, CD61, CD65, and 7.1, which were obtained from Immunotech (Marseille, France), and anti-TDT, MPO, CD79a, and anti-human Igμ heavy chains, which were purchased from DakoCytomation (Glostrup, Denmark). Data acquisition was performed using the CellQUEST software program (BDB) and information on a minimum of 15 000 events/tube from the total BM cellularity was acquired. In all cases, for the specific analysis of the phenotype of blast cells, appropriate CD19+/SSClow/int gating strategies were used, as reported previously.20 For data analysis, the PAINT-A-GATE PRO software (BDB) was used. Antigen expression was evaluated as the mean fluorescence intensity (MFI) specifically obtained for each marker analyzed after subtracting baseline autofluorescence levels.

Flow cytometry DNA ploidy studies

Flow cytometry DNA ploidy studies were performed in BM samples at diagnosis using the Cycloscope LLA reagent kit (Vitro, Madrid, Spain), strictly following the recommendations of the manufacturer. Measurements of cell DNA contents were performed on a FACSCalibur flow cytometer according to well-established methods.21 A case was considered to display DNA aneuploidy when G0/G1-phase blast cells showed a different DNA content than that of the normal residual G0/G1 cells present in the same BM sample. DNA index of blast cells was calculated as the ratio between the modal fluorescence intensity of G0/G1 blast cells and that of normal residual G0/G1 cells.

Statistical methods

The χ2 and Mann–Whitney U-tests were used to assess the statistical significance of differences observed between groups. Relapse-free survival (RFS) was calculated from the time of achieving CR to relapse/death or to the date of the last follow-up study. RFS curves were plotted according to the method of Kaplan–Meier; for the statistical comparison between RFS curves the log-rank test was used. Cases displaying one chromosomal abnormality were compared with those who were negative for it, independently of the coexistence of other alterations. Multivariate analysis of prognostic factors was performed using the Cox stepwise regression model to explore the independent effect of variables that showed a significant influence on RFS in the univariate analysis. Statistical significance was considered to be present once P-values were lower than 0.05.

Results and discussion

Genetic characteristics of BCP–ALL patients at diagnosis and their distribution

From the 46 adult ‘de novo’ BCR/ABL+ BCP–ALL cases included in this study, most showed Minor (m) BCR breakpoints (n=34; 76%), while the others corresponded to Major (M) bcr/abl gene rearrangements (n=11; 24%), except one case which had both p190 and p210 transcripts. Additional genetic abnormalities detected by iFISH included supernumerary Ph (n=14, 30%), trisomy 8 (n=9, 20%), monosomy 7 (n=7, 15%), and either heterozygous (n=8, 17%) or homozygous (n=3, 7%) 9p21 deletion (n=11, 24%), an incidence clearly higher than that found by conventional cytogenetics for the same abnormalities, as shown in Table 1 (13%, 13%, 8%, and 0%, of the 39 cases with available metaphases, respectively). It should be noted that metaphase FISH confirmed the presence of bcr/abl gene rearrangements in two of four BCR/ABL+ cases by iFISH in whom t(9;22) was not observed by conventional karyotyping. Overall, these results would support the higher sensitivity of iFISH as compared to conventional cytogenetics for the identification of these abnormalities, particulary of del(9p21). However, despite its higher sensitivity, iFISH only analyses selective chromosomal abnormalities while conventional karyotype explores the whole tumor cell genome. In line with previous publications,7 the frequency of DNA aneuploid cases was significantly higher among BCP–ALL cases showing duplication of the Ph chromosome as compared to the other BCR/ABL+ cases (67 vs 5%, P<0.001) (Table 1).

Table 1 Clinical, cytogenetic, iFISH findings and DNA ploidy from 46 adult patients with ‘de novo’ BCP–ALL

For over a decade, it has been well known that BCR/ABL+ BCP–ALL is a genetically heterogeneous disease, as confirmed in the present study. In most studies, conventional cytogenetic techniques have been used for the analysis of the karyotype of these patients allowing the identification of most of the abnormalities. However, these techniques fail to detect them in a significant proportion of cases due to the presence of normal or inadequate metaphases or limited sensitivity,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 also confirmed by our study.

Immunophenotype and genetic characteristics of BCR/ABL+ cells

In all cases studied, blast cells showed a precursor B-cell CD10+ common (BII) immunophenotype. In addition, all cases were also CD19+, CD34high, and Tdt+; they also presented a relatively heterogeneous CD38 expression and showed frequent reactivity for CD13 (80%) and/or CD33 (57%). Previous studies have shown a clear association between this immunophenotype of blast cells and the presence of underlying bcr/abl gene rearrangements in adult BCP–ALL, as confirmed here.20 However, no study has been reported so far in which the impact of additional genetic abnormalities on the phenotype of BCR/ABL+ blast cells has been systematically analyzed. In the present study, no clear immunophenotypic differences were found between MBCR+ as compared to mBCR+ cases. Nevertheless, we found that MBCR patients showed a lower CD10 expression on mature neutrophils as compared to mBCR+ cases (MFI of 98±67 vs 483±738; P=0.04), an abnormality that has been associated with myelodysplasic syndromes,22 suggesting additional involvement of other cell lineages. Interestingly, blast cells from patients with supernumerary Ph displayed a higher reactivity for CD19 (P=0.02) and CD22 (P=0.006); in a similar way, cases with trisomy 8 displayed a higher reactivity for the CD19 (P=0.01), CD34 (P<0.001), CD45 (P=0.009), and HLA-DR (P=0.01) antigens. By contrast, blast cells from cases with monosomy 7 showed a lower reactivity for CD19 (P=0.02), CD22 (P=0.01), CD34 (P=0.03), cCD79 (P=0.004), whereas del(9p21) was associated with a lack of expression of both the CD13 (P=0.04) and CD33 (P=0.03) myeloid-related antigens (Figure 1). Regarding antigens found to be either overexpressed or underexpressed in cases with trisomy 8 and monosomy 7, it should be noted that none of them are coded in the altered chromosomes 8 and 7. For this reason, the mechanism for gain or loss of these antigens cannot be directly attributed to the underlying genetic abnormality; alternatively, they could be related to deregulation of other genes involved in the early B-cell maturation pathways located in these chromosomes (eg, c-myc and Ikaros).23 Further studies are necessary to clarify the exact mechanisms contributing to these phenotypic/genotypic associations.

Figure 1
figure1

De novo’ BCP–ALL: Immunophenotypic differences between blast cells, according to the presence or absence of supernumerary Ph (panels a, b), trisomy 8 (panels c–f), monosomy 7 (panels g–j) and 9p21 (panels k, l). No statistically significant differences were found for markers not shown in this figure. Boxes extend from the 25th to the 75th percentiles; the line in the middle and vertical lines represent median values and the 95% confidence interval, respectively. MFI: mean fluorescence intensity (arbitrary relative linear units scaled from 0 to 10.000). P-values were calculated using the Mann–Whitney U-test.

Clinical and biological characteristics of BCR/ABL+ BCP–ALL

Overall the patients studied had a mean age of 48±16 years (range: 21–81 years), 25 were males and 21 females (Table 1), most of them (74%) displaying a FAB L2 morphology. Less than one-third of the cases presented with organomegalies (hepatomegaly, 14%; splenomegaly, 23%; and lymphadenopathies, 20%). Anemia (<100 g hemoglobin/l) and/or thrombocytopenia (<100 × 109 platelets/l) were found in 59% and 65% of the cases, respectively. In general, adults with BCR/ABL+ BCP–ALL showed a very similar clinical and hematological picture at presentation, independently of the BCR breakpoint or the existence of additional underlying genetic lesions. Minor differences observed related to age (higher among MBCR+ patients; P=0.02), gender distribution (trisomy 8 was more frequently observed in males, while monosomy 7 was characteristic of female patients), the presence of splenomegaly (higher for cases with a supernumerary Ph), and serum LDH levels (lower among patients with 9p21) (Table 2).

Table 2 Clinical, biological and prognostic characteristics of BCR/ABL+de novo’ BCP–ALL patients according to the presence or absence of supernumerary Ph, trisomy 8, monosomy 7, and 9p21 abnormalities by iFISH

Although more than two-thirds of the cases achieved CR, overall they showed a poor clinical outcome with many individuals dying early after diagnosis. Nevertheless, the clinical behavior of the disease was relatively heterogeneous, with 22% of the patients surviving for more than 1 year after diagnosis. Actually, in the present study no clinical, biological, or phenotypic parameter, except the hemoglobin levels, showed an impact on RFS. These results would support previous observations made by others who could not identify any clinico-biologic prognostic factor for RFS in Ph+ ALL.1, 4, 9 Previous reports have found a worse prognosis for bcr/abl patients with an extra Ph chromosome,5, 6 monosomy 7,4 and del(9p21).24 In the present study we confirmed the worse prognosis of supernumerary Ph (P=0.05), trisomy 8 (P=0.01) and del(9p21) (P=0.0003), but not of monosomy 7 (Figure 2); multivariate analysis of prognostic factors showed that only del(9p21) had an independent prognostic value for RFS, all patients displaying this genetic abnormality relapsing within a year as opposed to a RFS of more than 2 years for one-third of the cases with no del(9p21) (Figure 2). Several tumor suppressor genes involved in controlling cell growth and cell death, such us p16INK4a, p15INK4b, and p14ARF, are located at 9p21. Accordingly, the worse prognosis found for cases with del(9p21) may reflect an additional deregulation of cell proliferation, as has also been suggested for the occurrence of trisomy 8 in Ph+ CML patients. If the independent prognostic impact of del(9p21) is confirmed in other series, it will provide an attractive framework for the stratification of BCR/ABL+ BCP–ALL patients and the investigation of new targeted therapeutic strategies.

Figure 2
figure2

RFS curves of BCR/ABL+ BCP–ALL patients according to the presence or absence of supernumerary Ph (panel a), trisomy 8 (panel b), monosomy 7 (panel c) and 9p21 (panel d).

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Acknowledgements

MD Tabernero is supported by a grant from the Ministerio de Ciencia y Tecnología MCYT, (programa Ramón y Cajal), Madrid, Spain. JM Sayagues and AB Espinosa are supported by grants 02/9103 and 02/0010 from the Ministerio de Sanidad y Consumo (Madrid, Spain).

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Correspondence to A Orfao.

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Primo, D., Tabernero, M., Perez, J. et al. Genetic heterogeneity of BCR/ABL+ adult B-cell precursor acute lymphoblastic leukemia: impact on the clinical, biological and immunophenotypical disease characteristics. Leukemia 19, 713–720 (2005) doi:10.1038/sj.leu.2403714

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Keywords

  • BCP–ALL
  • Ph chromosome
  • FISH
  • del(9p21)
  • trisomy 8
  • monosomy 7

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