The poor prognostic significance of deletions of derivative chromosome 9 in Chinese patients with chronic myelogenous leukemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17535-17535
Author(s):  
J. Li ◽  
W. Xu ◽  
W. Wu ◽  
S. Zhang ◽  
Y. Zhu
Keyword(s):  
Fusion Gene ◽  
Hematologic Malignancy ◽  
Blast Crisis ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chinese Patients ◽  
Striking Difference ◽  
Derivative Chromosome

17535 Background: Chronic myeloid leukemia (CML) is characterized by formation of the BCR/ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Deletions of the derivative 9 chromosome [der(9)] in 10- 15% of CML patients with a standard Ph translocation and in >30% of CML patients with a variant Ph translocation. Subsequent studies demonstrated that CML patients who carry a der(9) deletion progress more rapidly to blast crisis and have a shorter survival than those without a deletion. The characteristics of Chinese patients with each hematologic malignancy compared with those in other countries have not yet been clarified. This prompted us to perform molecular and cytogenetic analyses on Chinese patients with CML. Methods: To study the incidence and the prognostic significance of the derivative chromosome 9 [der(9)] deletions in on Chinese patients with CML, a series of 48 BCR/ABL positive Chinese CML blast crisis (CML-BC) patients were investigated using dual colour dual fusion BCR/ABL probe and fluorescence in situ hybridization (FISH). Results: Eight (16.7%) cases showed der(9) deletions, and the deletions were also existed in chromosome preparations made at diagnosis. The estimated median length of chronic phase for patients with der(9) deletions was 18 months (range 4–38 months) compared to 48 months (range 0–204 months) for patients without deletions. Kaplan-Meier analysis revealed a striking difference in length of chronic phase between with and without der(9) deletions, and this difference was highly significant by log-rank analysis. Der(9) deletions are not associated with increased karyotypic instability. There was no difference in the probability of the der(9) deletions between the cases transformed to acute nonlymphocytic leukemia (ANLL) and those to acute lymphoid leukemia (ALL). Conclusions: The results indicate that FISH technique could effectively detect the der(9) deletions. Der(9) deletions occur at the time of Ph translocation. CML patients with der(9) deletions have more rapid process and poorer prognosis. Deletion status is a powerful prognostic factor for patients with CML. Der(9) deletions might not lead to transformation to specific type in CML. No significant financial relationships to disclose.

scholarly journals Detection of derivative 9 deletion by BCR-ABL fluorescence in-situ hybridization signal pattern to evaluate treatment response in CML patients

2009 ◽  
Vol 17 (1-2) ◽  
pp. 13-18
Author(s):  
Beena Patel ◽  
Pina Trivedi ◽  
Manisha Brahmbhatt ◽  
Sarju Gajjar ◽  
Ramesh Iyer ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Response To Therapy ◽  
Chromosome 9 ◽  
Derivative Chromosome ◽  
Partial Responder ◽  
Signal Pattern ◽  
Fish Signal

Background: To evaluate prognostic effect of submicroscopic deletions involving breakage and fusion points of the derivative chromosome 9 and 22 in chronic myeloid leukemia in untreated patients and their follow up samples to correlate with disease outcome. Methods: The study included 78 pretreatment (PT) samples from CML patients and 90 follow-up samples, classified as complete responders (CR, n=33), nonresponders (NR, n =54), and partial responder (PR, n=3) depending on the treatment status of the follow-up samples. Karyotype analysis was performed on metaphases obtained through short term cultures of bone marrow and blood. Detection of BCR-ABL fusion gene was performed using dual color dual fusion (D-FISH) translocation probes. Results: BCR-ABL fusion gene detection by D-FISH showed ABL-BCR deletion on derivative 9 in 47.8% of nonresponders which was higher as compared to pretreatment (11%). Mix D-FISH signal pattern was found in around 20% of pretreatment and non-responder samples. Average interval from chronic phase to blast crisis and accelerated phase was respectively 3.5 and 18 months and accelerated to blast crisis was 16.5 months from the time of diagnosis. The follow-up duration of 31 patients responded to therapy was significantly higher (p=0.0001) as compared to 45 patients who did not respond to therapy. Variant D-FISH signal pattern was seen at the time of diagnosis in patient who responded to therapy as well as those patients who did not respond to therapy. Conclusion: This is the first study from India reporting deletion in ABL, BCR, or ABL-BCR on derivative 9 did not correlate with response to therapy.

scholarly journals Relationship of bcr breakpoint to chronic phase duration, survival, and blast crisis lineage in chronic myelogenous leukemia patients presenting in early chronic phase [see comments]

Blood ◽  
1990 ◽  
Vol 75 (10) ◽  
pp. 2035-2041
Author(s):  
SW Morris ◽  
L Daniel ◽  
CM Ahmed ◽  
A Elias ◽  
P Lebowitz
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Fusion Gene ◽  
Blast Crisis ◽  
Cell Lineage ◽  
Chimeric Protein ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Phase Duration ◽  
Total Survival

Strong evidence implicates fusion of control elements and 5′ sequences of the bcr gene of chromosome 22 with 3′ sequences of the c-abl gene of chromosome 9 in the pathogenesis of Ph-positive and certain cases of Ph- negative chronic myelogenous leukemia (CML). Since this fusion gene gives rise to a chimeric tyrosine protein kinase with transforming potential, and since the bcr exon contribution to this chimeric protein is variable, the question has arisen as to whether bcr breakpoint location and bcr exon contribution could influence the clinical course of CML. Prior studies have yielded conflicting results on this point. Here we have looked, in a manner approximating a prospective analysis, at the relation of bcr breakpoint localization to the duration of chronic phase, total survival, and blast crisis phenotype in 81 patients presenting in the chronic phase of CML. We have found no significant differences in chronic phase duration or total survival among patients with breakpoints in the three major subregions of a breakpoint cluster region within the bcr gene. These findings indicate that chronic phase duration and total survival cannot be predicted from bcr breakpoint for CML patients presenting in chronic phase and suggest that unknown oncogenic events determining the onset of blast crisis are the prime determinants of prognosis. Combined analysis of blast crisis cell lineage in our patients and patients presented in a previous study has revealed an overall ratio of myeloid:lymphoid (M:L) crisis of 3.4:1, but a striking predominance of myeloid crisis in patients with breakpoints in subregion 2 (M:L of 9:1), and a lower than expected M:L ratio (1.6:1) among patients with breakpoints in subregion 3 (P for subregion 2 versus 3 = .012; subregions 0,1,2 versus 3 = .012; subregions 0,1,3 versus 2 = .032). The molecular basis for this divergence from the anticipated M:L ratio in patients with breakpoints in bcr subregions 2 and 3 is unknown.

Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2281-2286 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Moshe Talpaz ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Response Duration ◽  
Cytogenetic Response ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Derivative Chromosome

AbstractDeletions of derivative chromosome 9 [der(9)] can be identified by fluorescence in situ hybridization (FISH) in 10% to 15% of patients with chronic myeloid leukemia (CML). Patients with der(9) deletions have been reported to have an adverse outcome when treated with chemotherapy, interferon, and possibly imatinib mesylate. We investigated the frequency and prognostic significance of der(9) deletions among 352 patients with CML treated with imatinib mesylate at our institution, in whom a deletion status of der(9) was determined. Thirty-three patients (9%; 95% CI 0.07, 0.13) (30 in chronic phase, 3 in accelerated phase) had der(9) deletions. The rates of major (82% vs 79%, P = 0.82) and complete cytogenetic response (76% vs 66%, P = .33) with imatinib mesylate therapy were similar in patients with and without der(9) deletions, respectively. After a median follow-up of 28 months, there was no difference in overall survival (P = .30) or response duration (P = .49) in patients with and without deletions. In a multivariate analysis, der(9) deletions had no significant impact on response, survival, or response duration. We conclude that treatment with imatinib mesylate overcomes the adverse prognostic significance of der(9) deletions in patients with CML.

scholarly journals Relationship of bcr breakpoint to chronic phase duration, survival, and blast crisis lineage in chronic myelogenous leukemia patients presenting in early chronic phase [see comments]

Blood ◽  
1990 ◽  
Vol 75 (10) ◽  
pp. 2035-2041 ◽  
Author(s):  
SW Morris ◽  
L Daniel ◽  
CM Ahmed ◽  
A Elias ◽  
P Lebowitz
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Fusion Gene ◽  
Blast Crisis ◽  
Cell Lineage ◽  
Chimeric Protein ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Phase Duration ◽  
Total Survival

Abstract Strong evidence implicates fusion of control elements and 5′ sequences of the bcr gene of chromosome 22 with 3′ sequences of the c-abl gene of chromosome 9 in the pathogenesis of Ph-positive and certain cases of Ph- negative chronic myelogenous leukemia (CML). Since this fusion gene gives rise to a chimeric tyrosine protein kinase with transforming potential, and since the bcr exon contribution to this chimeric protein is variable, the question has arisen as to whether bcr breakpoint location and bcr exon contribution could influence the clinical course of CML. Prior studies have yielded conflicting results on this point. Here we have looked, in a manner approximating a prospective analysis, at the relation of bcr breakpoint localization to the duration of chronic phase, total survival, and blast crisis phenotype in 81 patients presenting in the chronic phase of CML. We have found no significant differences in chronic phase duration or total survival among patients with breakpoints in the three major subregions of a breakpoint cluster region within the bcr gene. These findings indicate that chronic phase duration and total survival cannot be predicted from bcr breakpoint for CML patients presenting in chronic phase and suggest that unknown oncogenic events determining the onset of blast crisis are the prime determinants of prognosis. Combined analysis of blast crisis cell lineage in our patients and patients presented in a previous study has revealed an overall ratio of myeloid:lymphoid (M:L) crisis of 3.4:1, but a striking predominance of myeloid crisis in patients with breakpoints in subregion 2 (M:L of 9:1), and a lower than expected M:L ratio (1.6:1) among patients with breakpoints in subregion 3 (P for subregion 2 versus 3 = .012; subregions 0,1,2 versus 3 = .012; subregions 0,1,3 versus 2 = .032). The molecular basis for this divergence from the anticipated M:L ratio in patients with breakpoints in bcr subregions 2 and 3 is unknown.

scholarly journals CML patients in blast crisis have breakpoints localized to a specific region of the BCR

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 448-455 ◽  
Author(s):  
K Schaefer-Rego ◽  
H Dudek ◽  
D Popenoe ◽  
Z Arlin ◽  
JG Mears ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Fusion Gene ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Large Area ◽  
Translocation Breakpoints ◽  
Ph Chromosome

Chronic myelogenous leukemia (CML) is associated with the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between chromosomes 9 and 22. This activates the abl oncogene by moving it from chromosome 9 and combining it with sequence located on chromosome 22. The new fusion gene, with chromosome 22 sequence at its 5′ end and chromosome 9-abl sequence at its 3′ end, generates a new messenger RNA (mRNA) and protein that are implicated in the pathogenesis of CML. The breakpoint near the c-abl locus on chromosome 9 can occur within a large area. In contrast, the breakpoints on chromosome 22 are concentrated within a 6 kilobase (kb) region termed the breakpoint cluster region (bcr). This study was designed to determine whether chronic-phase and blast crisis patients had identifiable differences in the structure of their Ph chromosomes. Restriction mapping of the chromosome 22 translocation breakpoints performed for 26 patients showed that the breakpoints of eight of the nine patients in blast crisis were in the 3′ portion of the bcr, whereas the breakpoints in the 17 patients in the chronic phase were clustered in the 5′ portion of the bcr. This suggests a strong correlation between a 3′ bcr breakpoint and blast crisis in CML.

scholarly journals CML patients in blast crisis have breakpoints localized to a specific region of the BCR

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 448-455 ◽  
Author(s):  
K Schaefer-Rego ◽  
H Dudek ◽  
D Popenoe ◽  
Z Arlin ◽  
JG Mears ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Fusion Gene ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Large Area ◽  
Translocation Breakpoints ◽  
Ph Chromosome

Abstract Chronic myelogenous leukemia (CML) is associated with the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between chromosomes 9 and 22. This activates the abl oncogene by moving it from chromosome 9 and combining it with sequence located on chromosome 22. The new fusion gene, with chromosome 22 sequence at its 5′ end and chromosome 9-abl sequence at its 3′ end, generates a new messenger RNA (mRNA) and protein that are implicated in the pathogenesis of CML. The breakpoint near the c-abl locus on chromosome 9 can occur within a large area. In contrast, the breakpoints on chromosome 22 are concentrated within a 6 kilobase (kb) region termed the breakpoint cluster region (bcr). This study was designed to determine whether chronic-phase and blast crisis patients had identifiable differences in the structure of their Ph chromosomes. Restriction mapping of the chromosome 22 translocation breakpoints performed for 26 patients showed that the breakpoints of eight of the nine patients in blast crisis were in the 3′ portion of the bcr, whereas the breakpoints in the 17 patients in the chronic phase were clustered in the 5′ portion of the bcr. This suggests a strong correlation between a 3′ bcr breakpoint and blast crisis in CML.

Prognostic Impact of Deletions of Derivative Chromosome 9 on Patients (PTS) with Chronic Myelogenous Leukemia (CML) in Chronic Phase Treated with Nilotinib or Dasatinib.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2110-2110
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop M. Kantarjian ◽  
Susan O’Brien ◽  
Gautam Borthakur ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Derivative Chromosome ◽  
2Nd Generation ◽  
Translocation Breakpoints

Abstract Background: Submicroscopic deletions of the derivative chromosome 9 [Del der(9)] mapping to regions adjacent to the translocation breakpoints occur in 9% to 15% of patients with CML. Del der(9) is a powerful prognostic indicator associated with unfavorable prognosis in patients treated with interferon-alpha (IFN-α)-based therapies. Imatinib is currently the standard treatment for patients with CML and it appears to overcome the adverse prognostic impact imparted by Del der(9). Methods: We investigated the prognostic impact of Del der(9) in 353 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=161) or dasatinib (n=192). The presence of Del der(9) prior to 2nd generation TKIs was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 245 patients. The median age was 53 years (range, 15–83) and the median follow-up was 24 months (range, 1–53). The primary endpoints evaluated were complete hematologic response (CHR), cytogenetic response, and survival. Results: Twenty-eight (11%) patients carried Del der(9) and 217 an intact der(9). Among patients with deletions, 22 were in chronic phase (CP), 4 in accelerated phase (AP), and 2 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 122 were in CP, 55 in AP and 40 in BP. Overall, 229 (93%) patients were assessable for response after a median of 25 months (range, 1–53) of therapy. The outcome by CML phase is shown in Table 1. CML phase Deletion der(9) No. CCyR (%) p EFS (12 mo) p OS (12 mo) p No 122 79 0.77 86 0.05 97 0.04 CP Yes 22 75 60 78 Not done 46 No 55 36 1.0 37 0.47 60 0.95 AP Yes 4 25 67 75 Not done 27 No 40 19 1.0 0 0.85 35 0.39 BP Yes 2 0 0 0 Not done 35 There was no difference in response rates among patients in CP, but those without Del der(9) had an improved EFS and OS at 24 months compared with those carrying Del der(9) (EFS: 86% vs 60%, p=0.05; OS: 97% vs 78%; p=0.04). Notably, whereas a trend towards worse EFS (p=0.05) and OS (p=0.12) was observed in patients in CP with Del der(9) treated with nilotinib, these outcomes were not significantly affected by Del der(9) in patients receiving dasatinib (EFS: p=0.47; OS: p=0.76). Conclusion: Our results suggest that, in contrast to what has been reported with imatinib therapy, patients with CML-CP carrying Del der(9) who failed imatinib may have a worse survival than their counterparts without deletions after treatment with 2nd generation TKI. This deleterious effect is more apparent among patients treated with nilotinib than among those receiving dasatinib.

Deletion of Any of BCR or ABL Gene on Derivative Chromosome 9 Is a Poor Prognostic Marker That Indicates Rapid Disease Progression in Chronic Myelogenous Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4471-4471
Author(s):  
Young Kyung Lee ◽  
Young Ree Kim ◽  
Cha Ja She ◽  
Sung-Soo Yoon ◽  
Young Soo Kim ◽  
...  
Keyword(s):  
Survival Time ◽  
Disease Progression ◽  
Prognostic Marker ◽  
Bone Marrow Cells ◽  
Prognostic Significance ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Derivative Chromosome ◽  
Rapid Disease Progression ◽  
Short Overall Survival

Abstract To evaluate the prognostic significance of the submicroscopic deletions of ABL or BCR gene associated with t(9;22) in CML, we investigated the incidence of ABL or BCR deletion on derivative chromosome 9 using fluorescent in situ hybridization (FISH), and analyzed the survival. FISH was performed using LSI BCR/ABL, dual fusion translocation probe on bone marrow cells of 86 patients with CML. Of 86 patients, ABL deletion was detected in 13 (15.1%) patients and BCR deletion in 8 patients (9.3%). Patients with ABL deletion showed shorter event-free survival time (EFS) than those without ABL deletion (P=0.020). Patients with BCR deletion showed significantly short overall survival time (OS) (P=0.039). Patients with ABL and/or BCR deletion (14/86 patients, 16.3%) showed significantly short OS and EFS (median OS: 43.0 months, median EFS: 40.0 months), compared to the patients without any deletions of BCR or ABL gene (median OS: 94.0 months, median EFS: 90.0 months)(P=0.041 for OS, P=0.008 for EFS). Patients with BCR deletion, all except one had a concomitant ABL deletion, suggesting that BCR deletion occurs in conjunction with ABL deletion. In patients with ABL deletion only, BCR/ABL rearrangement with b2a2 mRNA type tended to be more frequent than in patients without any deletion of the two genes (P=0.073). Deletion of any of BCR or ABL gene on derivative chromosome 9 was associated with both short OS and EFS. We conclude that deletion of not only ABL gene, but also BCR gene is a poor prognostic marker that indicates rapid disease progression in CML.

Heterogeneous Prognostic Impact of 9q+ Deletions in Patients with Chronic Myelogenous Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2111-2111
Author(s):  
Sebastian Kreil ◽  
Katherine Waghorn ◽  
Markus Pfirrmann ◽  
Andreas Reiter ◽  
Rudiger Hehlmann ◽  
...  
Keyword(s):  
Blood Platelets ◽  
Univariate Analysis ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Derivative Chromosome ◽  
German Studies ◽  
Reliable Technique ◽  
Significant Difference

Abstract Deletions at the ABL-BCR reciprocal breakpoint on the derivative chromosome 9 are seen in 10–15% of patients with CML and have been associated with a poor prognosis, at least for cases treated with hydroxyurea or interferon alpha (IFN). Studies to date have used different fluorescent-in-situ-hybridization (FISH) probe sets to determine deletion status and thus the results are not always directly comparable. Furthermore, information concerning the extent of deletions is limited and no studies have been performed in the context of a prospective randomised controlled clinical trial. To provide more accurate information about deletion status, we developed a rapid DNA-based screen based on multiplex ligation-dependent probe amplification (MLPA). Der(9) deletions were detected at dilutions of 60% or more MC3 cell DNA in non-deleted DNA, indicating that the method was suitable for analysis of samples with up to 40% normal cells. We then investigated 348 chronic phase (CP) patients that were treated with IFN based therapies in three consecutive prospective controlled German studies. The median duration of IFN-based treatment was 17 months (range, 1–115) with a median observation time of seven years (range, 0.3–16); 160 patients (46%) were alive at the date of analysis. Therapy subsequent to IFN included allogeneic stem cell transplantation (SCT; n=130) or imatinib mesylate (IM; n=62). DNA extracted at diagnosis was tested by MLPA and 9q+ deletions, defined as the loss of at least two consecutive markers, were found in 59/348 (17%) patients. Of these 59 deletions, 21 spanned the ABL-BCR breakpoint and 38 were either upstream only (n=20) or downstream only (n=18) of the breakpoint. Analysis of the baseline parameters age, spleen size, leukocyte count, % eosinophils, basophils and blasts in peripheral blood, platelets, hemoglobin, and prognostic scores according to Hasford and Sokal did not reveal any significant difference between patients with and without deletions. There was no significant difference in overall survival between patients with or without deletions and also no difference in survival when patients were censored at SCT in CP or IM treatment. Patients with large ABL-BCR deletions had a poorer survival compared to all other cases (5.7 vs 8.8 years; p=0.0025) but this fell below the level of significance using censored survival (p=0.08). Patients with low risk Sokal or Hasford scores with breakpoint spanning deletions had a significantly worse prognosis than other cases (p=0.01 and p=0.04, respectively). Patients with ABL-BCR deletions also showed a trend towards a less favourable survival after allogeneic SCT in CP-CML (p=0.06). Surprisingly, patients with deletions that did not span the breakpoint showed a superior outcome (p=0.02). Univariate analysis of baseline data revealed that patients with either ABL or BCR deletions only were younger, presented with more circulating blasts and a larger spleen at diagnosis. Patients with large deletions spanning the breakpoint had fewer additional chromosomal abnormalities. In conclusion, MLPA is a reliable technique for detection of der(9) deletions in CML. Our analysis indicates that only those deletions that span the reciprocal ABL-BCR breakpoint are associated with adverse prognosis but the effect is relatively weak.

Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1160-1168 ◽  
Author(s):  
Brian J. P. Huntly ◽  
Anthony Bench ◽  
Anthony R. Green
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Blast Crisis ◽  
Scoring Systems ◽  
Chromosome 9 ◽  
Rapid Progression ◽  
Molecular Heterogeneity ◽  
Derivative Chromosome ◽  
New Paradigm

Abstract Chronic myeloid leukemia (CML) is characterized by formation of a BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Recently the development of new fluorescence insitu hybridization (FISH) techniques has allowed identification of unexpected deletions of the reciprocal translocation product, the derivative chromosome 9, in 10% to 15% of patients with CML. These deletions are large, span the translocation breakpoint, and occur at the same time as the Ph translocation. Such deletions therefore give rise to previously unsuspected molecular heterogeneity from the very beginning of this disease, and there is mounting evidence for similar deletions associated with other translocations. Several studies have demonstrated that CML patients who carry derivative chromosome 9 deletions exhibit a more rapid progression to blast crisis and a shorter survival. Deletion status is independent of, and more powerful than, the Sokal and Hasford/European prognostic scoring systems. The poor prognosis associated with deletions is seen in patients treated with hydroxyurea or interferon, and preliminary evidence suggests that patients with deletions may also have a worse outcome than nondeleted patients following stem cell transplantation or treatment with imatinib. Poor outcome cannot be attributed to loss of the reciprocal ABL-BCR fusion gene expression alone, and is likely to reflect loss of one or more critical genes within the deleted region. The molecular heterogeneity associated with the Philadelphia translocation provides a new paradigm with potential relevance to all malignancies associated with reciprocal chromosomal translocations and/or fusion gene formation.

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