Derivative chromosome 9 deletions in chronic myeloid leukemia: poor prognosis is not associated with loss of ABL-BCRexpression, elevated BCR-ABL levels, or karyotypic instability

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4547-4553 ◽  
Author(s):  
Brian J. P. Huntly ◽  
Anthony J. Bench ◽  
Eric Delabesse ◽  
Alistair G. Reid ◽  
Juan Li ◽  
...  

Deletions of the derivative chromosome 9 have recently been reported in chronic myeloid leukemia. These deletions are large, occur at the time of the Philadelphia (Ph) translocation, span the translocation breakpoint, and represent a powerful prognostic indicator. However, the molecular mechanisms responsible for the poor prognosis associated with deletions are obscure, and several possible models are investigated here. First, we demonstrate that all derivative chromosome 9 deletions detected by fluorescence in situ hybridization were associated with an absence ofABL-BCR expression. However, loss ofABL-BCR expression also occurred without an overt deletion, suggesting the existence of other mechanisms by whichABL-BCR transcription can be abolished. Furthermore, analysis of survival in 160 patients demonstrated that loss ofABL-BCR expression, in contrast to deletion status, was not an indicator of poor prognosis. Second, we addressed the possibility that concomitant small deletions of the Ph chromosome modulateBCR-ABL transcription. Real-time reverse-transcription polymerase chain reaction was used to demonstrate that derivative chromosome 9 deletions were not accompanied by altered levels of BCR-ABL transcripts. Third, deletions may represent a consequence of genetic instability within the target cell at the time of the Ph translocation, with the poor prognosis reflecting a predisposition to subsequent additional genetic alterations. However, patients with deletions do not exhibit an increased frequency of secondary cytogenetic changes following disease progression. Taken together, these data support a model in which deletions of the derivative chromosome 9 result in rapid disease progression as a result of the loss of one or more genes within the deleted region.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2926-2926
Author(s):  
Francesco Albano ◽  
Luisa Anelli ◽  
Antonella Zagaria ◽  
Alessandra Pannunzio ◽  
Antonella Russo Rossi ◽  
...  

Abstract Deletions on der(9) are associated with chronic myeloid leukemia(CML) in 15–18% of cases. To date, the biological significance of this genomic loss in the pathogenesis of CML is unknown. The most plausible hypothesis is that the loss of a tumor suppressor gene may confer a proliferative advantage to the Philadelphia-positive clone. On the other hand, it has now become evident that microRNAs (miRNAs) play an important regulatory role in some hematological malignancies. To investigate the presence of miRNAs within the genomic regions lost on der(9) we analyzed 60 CML patients with der(9) deletions. Methods. Genomic characterization of the deleted sequences was performed by fluorescence in situ hybridization (FISH) using a contig of DNA clones; the miRBase (http://microrna.sanger.ac.uk/) was queried to assess the presence of miRNAs in the der(9) deleted genomic regions. FISH experiments showed that the genomic loss on der(9) of the 9 (centromeric to ABL) and 22 (telomeric to BCR) chromosome sequences ranged from 260 Kb to 54 Mb and from 230 Kb to 12.9 Mb, respectively. Consultation of the miRBase revealed that in 16 (27%) patients there was loss of miRNAs mapping on chromosome 9 whereas no known miRNAs were mapped on the deleted genomic sequences belonging to chromosome 22. Moreover, 4 cases with a complex t(9;22) rearrangement and der(9) deletions showed loss of the miRNAs sequence also on the third derivative chromosome (4p16, 7p14, 13q14, and 11q13, respectively); among them, only in one case the loss of miRNAs on the third derivative was not associated with the miRNAs deletion mapped on chromosome 9. The most recurrent miRNAs deleted on der(9) were mir-219–2 (deleted in 100% of cases) and mir-199-b (lost in 67% of cases). It is noteworthy that mir-219–2 neighbors and overlaps CpG-islands, suggesting a potential role of this miRNA in CpG-island methylation. Experimental studies indicate that miRNAs can function as tumor suppressor genes or as oncogenes. In fact, in chronic lymphocytic leukemia associated with del(13)(q14) it has been demonstrated that the miRNAs loss can induce downregulation of the antiapoptotic BCL-2 protein. The novel evidence that deletions on der(9) in CML are associated with miRNAs loss may shed new light on the significance of genomic sequences loss. Further studies are needed since it is known that some microRNAs may have as many as a few thousand targets, so prediction algorithms and strategies allowing large-scale screening of multiple target genes are required.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2860-2860
Author(s):  
Feng-Ming Tien ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Wen-Chien Chou ◽  
Chi-Cheng Li ◽  
...  

Abstract Introduction Acute myeloid leukemia (AML) with hyperleukocytosis (HL), commonly defined as white blood cell (WBC) counts >100,000/uL, are intuitively thought as a unique group with dismal prognosis. However, comprehensive studies regarding the clinical characteristics, genetic alterations in this group of patients are limited, and the role of hematopoietic stem cell transplantation (HSCT) is controversial. Method A cohort of 755 de novo AML patients diagnosed from 1994 to 2011 who had cryopreserved cells for analysis were enrolled. The mutation status of 18 genes was determined by Sanger sequencing and/or next generation sequencing (NGS). We compared cytogenetics and relevant mutations in these genes between AML patients with and without HL, and exposed their prognostic implications. Results The median age was 54 (range 15-94). 101 (13.4%) patients had HL. HL was associated with younger age (median age 47 vs. 54, P=0.022), higher peripheral blast percentage (77.6% vs. 39%, P<0.0001), and higher lactate dehydrogenase levels (1921.5 U/L vs. 778 U/L, P<0.0001). HL was correlated with French-American-British (FAB) M1, M4 or M5 subtypes, but inversely with M2 or M3 subtypes. The HL patients had more frequently AML with intermediate-risk cytogenetics (85.4 vs. 63.6%, P< 0.0001), but less commonly good-risk (9.3 vs. 21.7%, P=0.004) or poor-risk cytogenetic AML (5.2 vs. 14.6%, P=0.01). Specifically, HL occurred less frequently in core-binding factor AML, or complex karyotype. The most common molecular event in the patients with HL was FLT3/ITD (38.9%), followed by NPM1 (28.7%), CEBPA (26%), NRAS (20.9%), and TET2 (19.4%) mutations. The HL patients had significantly higher incidences of NPM1 (28.7% vs. 18.2%, P=0.013), FLT3/ITD(38.9% vs. 19.1%, P<0.0001), CEBPA (26% vs. 11.1%, P<0.0001), and TET2 (19.4% vs. 9.9%, P=0.006) mutations. In contrast, HL was mutually exclusive with KRAS mutations. Survival analysis was performed on the 525 patients who received standard intensive chemotherapy; among whom 69 patients had HL. The HL patients had lower complete remission (CR) rates compared to those without (63.8% vs. 78.2%, P=0.009). Further, the HL patients had significantly poorer overall survival (OS) and disease-free survival (DFS) than those without (median 24 months vs. not reached (NR), P=0.042; 6.5 vs. 11.8 months, P=0.005, respectively, Figure 1). Older age, poor-risk cytogenetics, RUNX1, TP53 and WT1 mutations were other poor prognostic factors for OS (median, 18.1 months vs. NR, P<0.0001; 8.5 months vs. NR, P<0.0001; 18 months vs. NR, P=0.001; 5.9 months vs. NR, P<0.0001; 14.0 months vs. NR, P=0.006, respectively) and DFS (median, 7.7 vs. 15.2 months, P=0.005; 0 vs. 12,2 months, P<0.0001; 5.2 vs. 12 months, P=0.001; 0 vs. 11.8 months, P<0.0001; 6.5 vs. 12 months, P=0.001, respectively). NPM1+/FLT3-ITD-, and biallelic CEBPA mutations were favourable prognostic factors for both OS and DFS. In the multivariate Cox proportional hazards regression analysis, HL was still an independent poor prognosis factor for OS and DFS (RR, 1.67; 95% CI, 1.15-2.43, P=0.007 and RR, 1.58; 95% CI, 1.12-2.25, P=0.010, respectively). Intriguingly, among the HL patients, those with HSCT had longer OS than those without (58.2 vs 10.7 months, P=0.004, Figure 2). Among the 172 patients receiving allogeneic HSCT, the poor prognostic impact of HL on OS and DFS was lost (P=0.832 and P=0.678, respectively). HSCT could ameliorate the poor survival impact of HL. Conclusion The HL patients represented 13.4% of our AML cohort and showed distinct clinic features and genetic alterations compared to those without HL. HL was an independent poor prognosis factor irrespective of cytogenetics change or mutation status, and the HL patients may potentially benefit from HSCT. Figure 1 The Kaplan-Meier survival curves for OS (A) and DFS (B) stratified by hyperleukocytosis (HL) or not in the 525 AML patients who received standard intensive chemotherapy (A) (B) Figure 1. The Kaplan-Meier survival curves for OS (A) and DFS (B) stratified by hyperleukocytosis (HL) or not in the 525 AML patients who received standard intensive chemotherapy. / (A). / (B) Figure 2 The Kaplan-Meier survival curves for OS stratified by HSCT or not in the 69 HL patients who received standard intensive chemotherapy Figure 2. The Kaplan-Meier survival curves for OS stratified by HSCT or not in the 69 HL patients who received standard intensive chemotherapy Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.


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