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.

Clinical and Interphase-FISH Studies of Deletion of Derivative Chromosome 9 in Patients with Chronic Myelogenous Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4482-4482
Author(s):  
Wei Wu ◽  
Yong-quan Xue ◽  
Ya-fang Wu ◽  
Jin-lan Pan ◽  
Juan Shen
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Derivative Chromosome ◽  
Interphase Fish ◽  
Significant Difference ◽  
Cytogenetical Analysis ◽  
Variant Ph Translocation

Abstract Objective: To determine the frequency of the deletion of derivative 9 [der(9)] among chronic myeloid leukemia (CML) patients with classic Ph translocation and variant Ph translocation, and to assess the association between this deletion and clinical prognosis. Methods: Cytogenetical analysis of bone marrow cells was performed by direct method and /or 24h culture method. RHG banding was used for karyotype analysis. Dual-color and dual-fusion DNA probe was used to perform interphase-FISH to investigate the deletion of der(9) in Ph+ CML patients and all patients were followed up. Result: Cytogenetical studies showed typical Ph translocation in 76/105 and variant Ph translocation in 29/105. Interphase-FISH studies showed deletion of der(9) in 12 cases(15.8%) of 76 patients with classic Ph translocation and in 4 cases (13.7%) of 29 patients with variant translocation. The frequency of deletion was similar in classic and variant translocations (P>0.9). This result is contrary to previous reports which suggested that deletions are much more common in variant Ph translocation than in classic Ph translocation. When the deletion was seen in a patient, it was present in all the Ph+ metaphases and nuclei. Three patients with heterogeneous cell populations mixed with cells with single 5′-ABL or 3′-BCR deletion and with both 5′-ABL and 3′-BCR deletion. It may suggest clone evolution in the progression of deletion. Complete clinical information was available in 54 patients. There were no significant difference in peripheral leukocyte count, platelet count, hemoglobin and percentage of peripheral blood blast cells between patients with and without der(9)deletion. However, the results of following up showed that the median survival time of patients with der(9) deletion was significantly shorter than those without der(9) deletion (34 months vs 76 months; P<0.05, log-rank Test). Conclusion: A deletion of der(9) is seen in about 1/6 Ph+ CML patients in china, with which Ph+ CML patients have shorter median survival time than those without it, indicating that it is a poor prognostic index. For evolution the prognosis of CML patients more precisely, it is best to perform cytogenetical analysis and FISH analysis for der(9) deletion simultaneously at diagnosis.

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.

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 by enzymatic amplification of bcr-abl mRNA in peripheral blood and bone marrow cells of patients with chronic myelogenous leukemia

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1735-1741 ◽  
Author(s):  
W Lange ◽  
DS Snyder ◽  
R Castro ◽  
JJ Rossi ◽  
KG Blume
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Bone Marrow Cells ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Enzymatic Amplification ◽  
Polymerase Chain ◽  
Marrow Cells

Abstract The Philadelphia chromosome of chronic myelogenous leukemia (CML) patients is caused by a translocation of the c-abl gene from chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22. A new bcr- abl mRNA is expressed in these cases. We have developed a modified polymerase chain reaction (PCR) for the detection of this mRNA. The method is extremely sensitive, reliable, and relatively fast. The analysis of peripheral blood or bone marrow cells from CML patients treated with chemotherapy shows that the two possible mRNAs are expressed in various combinations. Our results show that even after myeloablative therapy for bone marrow transplantation bcr-abl mRNAs are still expressed. Further studies, however, are necessary to determine the clinical relevance of a small number of persisting cells expressing the bcr-abl mRNA.

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.

Investigation Of p210 Bcr-Abl Rhogef Activity In The Progression Of Chronic Myelogenous Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3802-3802
Author(s):  
Bryan T Ciccarelli ◽  
Ilona Tala ◽  
Tinghui Hu ◽  
Dan Li ◽  
Ru Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Chronic Myelogenous Leukemia ◽  
Rho Gtpase ◽  
Lymphoblastic Leukemia ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Single Amino Acid ◽  
Functional Domain ◽  
Murine Bone Marrow

Abstract The Philadelphia chromosome is formed by a balanced, reciprocal translocation that pairs sequences from BCR on Chromosome 22 with sequences from ABL on Chromosome 9 and results in the production of the constituitively active tyrosine kinase Bcr-Abl. Depending on the location of the breakpoint within BCR, three different sizes of Bcr-Abl can be produced (i.e., p190, p210 and p230) and they are associated with different clinical outcomes. The larger p210 form is observed in greater-than 95% of chronic myelogenous leukemia [CML], while the diminutive p190 is present in approximately 2/3 of Philadelphia-positive acute lymphoblastic leukemia [ALL]. Although both the p210 and p190 forms contain the same portion of Abl, importantly, they differ only in the amount of Bcr which is retained at the amino terminus. We previously identified a functional domain within the Bcr sequences preserved by p210, but not by p190, which demonstrates a constitutive Rho GTPase-specific guanine nucleotide exchange factor [RhoGEF] activity. To determine the contribution of this region to p210 Bcr-Abl-related disease progression in CML, we therefore introduced a single amino acid substitution [S509A] into this construct which abrogated its activity and then compared this mutant to the p210 and p190 variants in a murine bone marrow transplantation model. While all of the mice eventually developed myeloproliferative disease, those transplanted with either p210 Bcr-Abl S509A or p190 Bcr-Abl displayed a more rapid onset than the mice transplanted with p210 Bcr-Abl (within 12 vs. 23 days of transplantation, respectively). Interestingly, this reduced disease latency is associated with erythroid hyperplasia in the absence of anemia and expansion of megakaryocyte-erythrocyte progenitor, common myeloid progenitor and granulocyte-macrophage progenitor populations, which results in a phenotype that is similar to the M6 form of acute myeloid leukemia. This phenotype is also readily transplantable into secondary recipients, indicating that it is a true element of the malignancy and not a reactive process. Taken together, these results support a model wherein the RhoGEF activity of p210 Bcr-Abl actively regulates disease progression by downregulating the self-renewal of myeloid progenitors. While our animal studies indicate that the Bcr region plays a significant role in disease progression, to the best of our knowledge, this has yet to be evaluated using clinically derived mutations. Recently, the RhoGEF domain of p210 Bcr-Abl was reported to be mutated and/or partially deleted in tumors obtained from several CML blast crisis patients and a p210 Bcr-Abl-positive ALL patient. These findings suggest that the RhoGEF domain of p210 Bcr-Abl may in fact be actively involved in the aggressiveness of primary specimens as well. In order to determine the consequences of the reported mutations, we therefore examined their effects on disease progression using a murine bone marrow transplant model. Disclosures: No relevant conflicts of interest to declare.

Inversion of Chromosome 12 and Translocations of 12q13-q15 In Primary Myelofibrosis (PMF) Are Associated with Disease Progression and a Poor Prognosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4110-4110 ◽  
Author(s):  
Vesna Najfeld ◽  
Joseph Tripodi ◽  
Nathaniel Wisch ◽  
Amory Novoselac ◽  
Heike L. Pahl ◽  
...  
Keyword(s):  
Stem Cell ◽  
Disease Progression ◽  
Poor Prognosis ◽  
Chromosomal Abnormalities ◽  
Prognostic Significance ◽  
Primary Myelofibrosis ◽  
Myelogenous Leukemia ◽  
Jak2v617f Mutation ◽  
Chromosome 12 ◽  
Band Region

Abstract Abstract 4110 Recurrent chromosomal abnormalities are occurring at the frequency of 45–50% among patients (pts) with primary myelofibrosis (PMF). The prognostic significance of these abnormalities is largely unknown. Among 377 pts (242 from the Mount Sinai Medical Center and 135 from the MPD-RC data base) with primary myelofibrosis (PMF) 187 pts (50%) were cytogenetically abnormal. Of these, 17 pts (9%) had abnormalities of chromosome 12. We postulated that chromosome 12 abnormalities have prognostic significance and investigated whether they are associated with progression of disease. The cohort included 13 males and 4 females with an average age of 55 years (range 26 to 74). The JAK2V617F mutation was present in 4 pts, was absent in 7 pts and in the remaining 6 pts the status was unknown. Four of 17 pts (23.5%) had a terminal deletion of band p12 on the short arms while the remaining 13 pts (76.5%) had structural aberrations of the long arms. Five pts (29%) had an inversion of chromosome 12: 3 pts had had a pericentric inversion involving the p12 band region on the short arms and q13 band region on the long arms; while 2 pts had a paracentric inversion involving q13 and q24 segments on the long arm. In 3 of 5 pts with inv(12)) two cytogenetic events occurred: first, the formation of an inversion followed by the translocation of 12q to another chromosome, indicating that this region(s) is under selective pressure for multiple genetic events. The most frequent partner chromosome in 12q translocations were chromosome 2 (3 pts), and chromosome 10 (3 pts). Since the q13 band region was involved in 77% (10 of 13) pts with 12q abnormalities including all 5 pts with inv(12) we postulated that the NF-E2 transcription factor, at the 12q13.13 chromosomal site, may be structurally rearranged. The NF-E2 expression is increased in PMF pts (Wang et al, Blood, 2010). RP11-968A15 BAC FISH probe, which containes the entire NF-E2 was hybridized to metaphase and interphase cells from 3 pts with inv (12) and 2 pts with 12q13 translocations. FISH analysis of over 1,000 cells showed a structurally intact NF-E2 in all 5pts without evidence of rearrangements or deletions. Disease progression, transformation to acute myelogenous leukemia (AML) and death was observed in 70% (7 of 10) of pts with 12q13 abnormalities and 2 additional pts with 12q15 chromosome aberrations. Therefore, region q13 to q15 on chromosome 12 is associated with a poor prognosis in 92% of patients with PMF. Specifically, 3 of 5 pts with inv(12) expired, one transformed to AML and the 5th pt underwent stem cell transplant. Both pts with 12q15 abnormalities transformed to AML, one of them expired. An additional 4 pts with advanced disease underwent SCT and are doing well after 5 to 18 months. Our observations demonstrated that 12q13-q15 chromosomal abnormalities are more frequent in males (3:1 ratio) and occurring in 40% of JAK2V617F mutation negative pts. The presence of inv(12) and/or translocations of 12q13-q15 at diagnosis is associated with disease progression in 92% of pts with PMF and therefore stem cell transplantation should be considered as a treatment option early in the disease course. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prognostic impact of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia treated with nilotinib or dasatinib

Cancer ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5085-5093 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Jianqin Shan ◽  
Elias Jabbour ◽  
Lynne V. Abruzzo ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Derivative Chromosome
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