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]

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.

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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 ◽

10.1182/blood.v75.10.2035.2035 ◽

1990 ◽

Vol 75 (10) ◽

pp. 2035-2041 ◽

Cited By ~ 39

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.17535 ◽

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.

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Imatinib Mesylate (STI 571) – A New Oral Target Therapy For Chronic Myelogenous Leukemia (CML)

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2019.12 ◽

2003 ◽

Vol 46 (3) ◽

pp. 85-89 ◽

Cited By ~ 2

Author(s):

Ladislav Chrobák ◽

Jaroslava Voglová

Keyword(s):

Imatinib Mesylate ◽

Chronic Myelogenous Leukemia ◽

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Blast Crisis ◽

Chronic Phase ◽

New Drugs ◽

Myelogenous Leukemia ◽

Treatment Modalities ◽

Sti 571

The publication provides an up-to-date review of the significance of cytogenetic abnormalities in chronic myelogenous leukemia (CML) and the development of a promising agent with specific molecular target against tyrosine kinase, product of the BCR-ABL fusion gene, namely imatinib mesylate (STI 571, Glivec). The publication summarizes the achieved results with this compound in the chronic phase CML (in patients resistant to interferon and in newly diagnosed patients) further in patients in the accelerated phase and in blast crisis and in patients in relapse after allogeneic stem cells transplantations for CML. The results in Ph+ acute lymphoblastic leukemia are also presented. The mechanisms of resistance to imatinib mesylate and the possibilities how to overcome or circumvent it are mentioned (escalation of the dosage, combination of imatinib with some other treatment modalities as immunotherapy, interferon or convention chemotherapy and development of new drugs).

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

Blood ◽

10.1182/blood.v70.2.448.bloodjournal702448 ◽

1987 ◽

Vol 70 (2) ◽

pp. 448-455 ◽

Cited By ~ 1

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.

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

Blood ◽

10.1182/blood.v70.2.448.448 ◽

1987 ◽

Vol 70 (2) ◽

pp. 448-455 ◽

Cited By ~ 71

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.

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Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia [see comments]

Blood ◽

10.1182/blood.v83.12.3449.3449 ◽

1994 ◽

Vol 83 (12) ◽

pp. 3449-3456 ◽

Cited By ~ 90

Author(s):

C Wada ◽

S Shionoya ◽

Y Fujino ◽

H Tokuhiro ◽

T Akahoshi ◽

...

Keyword(s):

Genomic Instability ◽

Chronic Myelogenous Leukemia ◽

Blast Crisis ◽

Chronic Phase ◽

Genetic Alterations ◽

Myelogenous Leukemia ◽

Leukemic Cells ◽

Genetic Event ◽

Familial Predisposition ◽

Somatic Instability

Abstract Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor-suppressor genes. Investigation of genomic instability of microsatellites has indicated a new mechanism for human carcinogenesis in hereditary nonpolyposis colorectal cancer and sporadic cancer and this instability has been shown to be related to inherited predisposition to cancer. This study was conducted to determine whether such microsatellite instability is associated with the evolution of chronic myelogenous leukemia (CML) to the blast crisis. Nineteen CML patients clinically progressing from the chronic phase to accelerated phase or blast crisis and 20 other patients in the CML chronic phase were studied. By polymerase chain reaction assay, DNAs for genomic instability in five separate microsatellites in chromosome arms 5q (Mfd27), 17p (Mfd41), 18q (DCC), 3p (CI3–9), and 8p (LPL) were examined. Differences in unrelated microsatellites of chronic and blastic phase DNAs in 14 of 19 patients (73.7%) were demonstrated. Somatic instability in five microsatellites, Mfd27, Mfd41, DCC, CI3–9, and LPL, was detected in 2 of 19 (10.5%), 8 of 19 (42.1%), 11 of 19 (57.9%), 4 of 17 (23.5%), and 4 of 17 (23.5%) cases. In 10 of 19 cases (52.6%), genetic instability in at least two of five microsatellites was observed and was categorized as replication error (RER+) phenotype. CML evolution cases with myeloid, lymphoid, and mixed phenotypes and the blast crisis and accelerated phase showed somatic instability in a number of microsatellites. No alterations in leukemic cells at the chronic phase could be detected in any microsatellites. These data indicate instability of microsatellites (RER+) but not familial predisposition to possibly be a late genetic event in the evolution of CML to blast crisis. In the microsatellite of the DCC gene, complicated alterations in band patterns caused by instability as well as loss of heterozygosity (LOH) were observed in 13 of 19 cases (68.4%): instability in 9 cases, instability plus LOH in 2 cases, and only LOH in 2 cases. These highly frequent alterations in microsatellites, including instability and LOH, suggesting that secondary events due possibly to loss of fidelity in replication and repair machinery may be significantly associated with CML evolution.

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Mutations of the N-ras gene in juvenile chronic myelogenous leukemia

Blood ◽

10.1182/blood.v83.8.2248.bloodjournal8382248 ◽

1994 ◽

Vol 83 (8) ◽

pp. 2248-2254 ◽

Cited By ~ 5

Author(s):

J Miyauchi ◽

M Asada ◽

M Sasaki ◽

Y Tsunematsu ◽

S Kojima ◽

...

Keyword(s):

Sequence Analysis ◽

Chronic Myelogenous Leukemia ◽

Blast Crisis ◽

Gene Mutations ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Disease Stage ◽

Nucleotide Sequence Analysis ◽

Age Group ◽

Ras Gene

Juvenile chronic myelogenous leukemia (JCML), a myeloproliferative disorder of childhood, is distinct from adult-type chronic myelogenous leukemia (CML) and bears resemblance to chronic myelomonocytic leukemia (CMMoL). Since mutations in the N-ras gene have been found at high frequencies in CMMoL, but only rarely in CML, we analyzed mutations activating the N-ras gene in 20 patients with JCML. We used the strategy for analysis of gene mutations based on in vitro DNA amplification by polymerase chain reaction (PCR) followed by single- strand conformation polymorphism (SSCP) analysis and/or direct sequence analysis. Nucleotide sequence analysis showed single nucleotide substitutions involving codons 12, 13, or 61 in six of 20 patients (30%). Four of six patients with mutations were in chronic phase and the other two in blast crisis, indicating no apparent correlation with disease stage. Most of the patients with mutations were in the older age group with poor prognosis, although one patient in the younger age group also harbored the mutation. These data suggest that N-ras gene mutations may be involved in the pathogenesis and/or prognosis of JCML and provide further evidence that JCML is an entity distinct from CML.

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BCR Rearrangement–Negative Chronic Myelogenous Leukemia Revisited

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.11.2915 ◽

2001 ◽

Vol 19 (11) ◽

pp. 2915-2926 ◽

Cited By ~ 62

Author(s):

Razelle Kurzrock ◽

Carlos E. Bueso-Ramos ◽

Hagop Kantarjian ◽

Emil Freireich ◽

Susan L. Tucker ◽

...

Keyword(s):

Chronic Myelogenous Leukemia ◽

Blast Crisis ◽

Chronic Phase ◽

Interferon Alfa ◽

Myelogenous Leukemia ◽

Disease Evolution ◽

Number Of Patients ◽

Significant Difference ◽

Atypical Cml ◽

Peripheral Blood Smears

PURPOSE: To document the characteristics of patients with major breakpoint cluster region (M-bcr) rearrangement–negative chronic myelogenous leukemia (CML). PATIENTS AND METHODS: The hematopathologist, who was blinded to patients’ molecular status, reviewed the referral bone marrows and peripheral-blood smears from 26 patients with Philadelphia (Ph) translocation–negative CML who lacked Bcr rearrangement (and other evidence of a Bcr-Abl anomaly) and 14 patients (controls) with chronic-phase Ph-positive CML. Clinical data was ascertained by chart review. RESULTS: Among the 26 M-bcr rearrangement–negative CML patients, three pathologic subtypes emerged: (1) patients indistinguishable from classic CML (n = 9), (2) patients with atypical CML (n = 8), and (3) patients with chronic neutrophilic leukemia (n = 9). Among the 14 patients with Ph-positive CML who were included in the blinded review, 13 were classified as classic CML, and one was classified as atypical CML. The only statistically significant difference between M-bcr rearrangement–negative subgroups was in the proportion of patients having karyotypic abnormalities, an observation common only in patients with atypical CML (P = 0.008). However, the small number of patients in each subgroup limited our ability to differentiate between them. Interferon alfa induced complete hematologic remission in five of 14 patients; four of these remissions lasted more than 5 years. Only one of 26 patients developed blast crisis. The median survival of the 26 patients was 37 months. CONCLUSION: Patients with M-bcr rearrangement–negative CML fall into three morphologic subgroups. Disease evolution does not generally involve blastic transformation. Instead, patients show progressive organomegaly, leukocytosis, anemia, and thrombocytosis. Some patients in each subgroup can respond to interferon alfa.

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Multi-unit ribozyme-mediated cleavage of bcr-abl mRNA in myeloid leukemias

Blood ◽

10.1182/blood.v85.8.2162.bloodjournal8582162 ◽

1995 ◽

Vol 85 (8) ◽

pp. 2162-2170 ◽

Cited By ~ 61

Author(s):

LH Leopold ◽

SK Shore ◽

TA Newkirk ◽

RM Reddy ◽

EP Reddy

Keyword(s):

Chronic Myelogenous Leukemia ◽

Fusion Gene ◽

Folate Receptor ◽

Philadelphia Chromosome ◽

Chromosome 9 ◽

Myelogenous Leukemia ◽

Myeloid Leukemias ◽

Transforming Activity ◽

Cleavage Reactions

Chronic myelogenous leukemia is characterized by the Philadelphia chromosome, which at the molecular level results from the fusion of the bcr gene on chromosome 22 and the abl gene on chromosome 9. The bcr-abl fusion gene encodes a novel tyrosine kinase with transforming activity. In this study, we have synthesized a multi-unti ribozyme that targets bcr-abl mRNA. In vitro ribozyme cleavage reactions show increased cleavage efficiency of this multi-unit ribozyme compared with single or double ribozymes. The multiunit ribozyme was then transfected into murine myeloblasts transformed with the bcr-abl gene (32D cells). Ribozyme transfection was accomplished either by liposomes or using follic acid-polylysine as a carrier. Multi-unit ribozyme transfection reduced the level of bcr-abl mRNA 3 logs when transfected via folate receptor-mediated uptake into transformed 32D cells. These results suggest that a multi-unit ribozyme could be an effective therapeutic agent for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia.

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