scholarly journals Frequent and extensive deletion during the 9,22 translocation in CML

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1123-1128 ◽  
Author(s):  
DW Popenoe ◽  
K Schaefer-Rego ◽  
JG Mears ◽  
A Bank ◽  
D Leibowitz
Keyword(s):  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Protein Product ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Related Protein ◽  
Limited Region ◽  
Cellular Oncogenes ◽  
The Individual ◽  
Rna Transcript

Abstract Chromosomal translocation is one mechanism by which cellular oncogenes may be activated during tumorigenesis. The translocation of the abl oncogene to the Philadelphia chromosome in chronic myelogenous leukemia (CML) results in a new RNA transcript that fuses sequence from chromosome 22 to sequence from the abl oncogene. This RNA presumably codes for a new abl-related protein product found in CML, the activity of which is different from the normal abl protein. The molecular structure of the translocation varies from patient to patient, and the individual variation in RNA transcript and protein product remains to be defined. This report describes the frequent occurrence of chromosomal deletion within the 9q+ chromosome during these translocations. The location of the deletions suggests that some mechanism maintains the chromosomal breakpoint on the Philadelphia chromosome within a limited region. These deletions complicate the interpretation of Southern blots as a means of detecting the translocation.

scholarly journals Frequent and extensive deletion during the 9,22 translocation in CML

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1123-1128 ◽  
Author(s):  
DW Popenoe ◽  
K Schaefer-Rego ◽  
JG Mears ◽  
A Bank ◽  
D Leibowitz
Keyword(s):  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Protein Product ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Related Protein ◽  
Limited Region ◽  
Cellular Oncogenes ◽  
The Individual ◽  
Rna Transcript

Chromosomal translocation is one mechanism by which cellular oncogenes may be activated during tumorigenesis. The translocation of the abl oncogene to the Philadelphia chromosome in chronic myelogenous leukemia (CML) results in a new RNA transcript that fuses sequence from chromosome 22 to sequence from the abl oncogene. This RNA presumably codes for a new abl-related protein product found in CML, the activity of which is different from the normal abl protein. The molecular structure of the translocation varies from patient to patient, and the individual variation in RNA transcript and protein product remains to be defined. This report describes the frequent occurrence of chromosomal deletion within the 9q+ chromosome during these translocations. The location of the deletions suggests that some mechanism maintains the chromosomal breakpoint on the Philadelphia chromosome within a limited region. These deletions complicate the interpretation of Southern blots as a means of detecting the translocation.

Nilotinib: A Review of its Use in Chronic Myelogenous Leukemia

2010 ◽  
Vol 2 ◽  
pp. CMT.S24
Author(s):  
Ting-Wei Lu ◽  
Ronan Swords ◽  
Francis J. Giles ◽  
Kevin Kelly
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Standard Of Care ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Large Randomized Control Trial ◽  
Prior Therapy ◽  
Frontline Treatment ◽  
Favourable Safety Profile

Chronic myeloid leukemia (CML) is characterized by the reciprocal chromosomal translocation, t(9;22), forming the BCR-ABL oncogene known as the Philadelphia chromosome. The development of imatinib, a small-molecule kinase inhibitor targeted against BCR-ABL, has revolutionized the management of CML and significantly improved the prognosis and outcome and until very recently was the standard of care in patients presenting with newly diagnosed CML. Nilotinib (Tasigna®) is an orally administered kinase inhibitor made by the Novartis Pharmaceuticals Corporation that was rationally designed to bind to the ABL kinase domain of BCR-ABL resulting in enhanced BCR-ABL inhibition. It is well tolerated and has a favourable safety profile. Nilotinib has been shown to be effective in patients who have failed prior therapy with imatinib. Recently a large randomized control trial comparing imatinib and nilotinib has demonstrated that niloitinb is superior to imatinib in the frontline treatment of CML. This review summarizes the preclinical and clinical data supporting the use of nilotinib in the frontline and secondline treatment of CML.

scholarly journals Analysis of breakpoints within the bcr gene and their correlation with the clinical course of Philadelphia-positive chronic myelogenous leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 485-490 ◽  
Author(s):  
M Shtalrid ◽  
M Talpaz ◽  
R Kurzrock ◽  
H Kantarjian ◽  
J Trujillo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Chronic Myelogenous Leukemia ◽  
Clinical Course ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Blastic Crisis ◽  
Phase Duration ◽  
Dna Fragment

Abstract Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between chromosomes 9 and 22. The breakpoints on chromosome 22 are clustered within a 5.8-kilobase (kb) DNA fragment known as the breakpoint cluster region (bcr), which encodes part of a functionally active gene. We analyzed the bcr in DNAs from 108 consecutive, unselected Philadelphia chromosome-positive CML patients by Southern blot and determined five restriction enzyme fragments within which breaks occur on chromosome 22. The exact sublocalization was determined in the DNA of 100 patients. It was found to be within the 5.8-kb in 99 patients and outside the bcr in only one. Within the bcr, most of the breakpoints occurred in fragments 1, 2, and 3. Overall, laboratory and clinical features of CML did not correlate with specific breakpoint fragments, but chronic-phase duration was longer in patients with a breakpoint in fragment 2 of the bcr. Large 3′ bcr deletions were found in nine patients but did not influence clinical outcome. DNA from one of six patients analyzed both during chronic phase and blastic crisis showed an additional aberrant fragment, which suggested that a second abnormal clone developed in blastic crisis.

scholarly journals Philadelphia-positive chronic myeloid leukemia with a chromosome 22 breakpoint outside the breakpoint cluster region [published erratum appears in Blood 1988 Jan;71(1):272]

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1659-1664 ◽  
Author(s):  
L Selleri ◽  
F Narni ◽  
G Emilia ◽  
A Colo ◽  
P Zucchini ◽  
...  
Keyword(s):  
Blot Analysis ◽  
Myeloid Leukemia ◽  
Northern Blot Analysis ◽  
Cdna Probe ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Transcriptional Unit ◽  
Chromosome 22 ◽  
Molecular Events ◽  
Translational Product

Abstract In chronic myelogenous leukemia (CML) the reciprocal translocation resulting in the Philadelphia chromosome (Ph1) leads to the formation of a chimeric transcriptional unit carrying both c-abl and bcr genetic information whose transcript is a new fused mRNA of 8.5-kilobases (kb) and whose translational product is a 210-kD phosphoprotein with tyrosine kinase activity implicated in the pathogenesis of CML. Twenty patients affected by Ph1-positive CML were studied by Southern blot analysis with bcr. Unexpectedly, in three Ph1-positive patients, the breakpoint of chromosome 22 was located neither inside the bcr region nor 5′ to it. Northern blot analysis of the RNAs of two of these patients showed the absence of a detectable 8.5-kb chimeric mRNA. In the third patient a chimeric mRNA was detected by a c-abl cDNA probe but failed to hybridize with a bcr cDNA probe and showed very low hybridization levels with further 5′ bcr cDNA probes. The possibility is raised that in CML a breakpoint outside bcr might either still allow the formation of a chimeric mRNA, possibly through alternative splicing mechanisms, or might prevent the transcription of the chimera. In the latter case different molecular events resulting in the formation of a Ph1 chromosome may underlie the same myeloid neoplastic phenotype.

scholarly journals Variable breakpoints on the Philadelphia chromosome in chronic myelogenous leukemia

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 243-245 ◽  
Author(s):  
D Leibowitz ◽  
K Schaefer-Rego ◽  
DW Popenoe ◽  
JG Mears ◽  
A Bank
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Southern Blotting ◽  
Philadelphia Chromosome ◽  
Dna Probes ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Human Dna ◽  
Translocation Breakpoints ◽  
The Creation

Abstract The abl oncogene is translocated from chromosome 9 to 22 in the creation of the Philadelphia (Ph1) chromosome. This article describes new translocation breakpoints identified in two patients with chronic myelogenous leukemia using Southern blotting and cloned human DNA probes from chromosome 9. The translocation breakpoints on chromosome 9 in both of these patients lie closer to the human cellular abl (c-abl) gene, and the chromosome 22 breakpoints are distributed more widely than previously reported. These data help to define more clearly the chromosomal span of the breakpoints and indicate that some translocations include very little chromosome 9 sequence located 5′ to the c-abl gene.

scholarly journals Analysis of breakpoints within the bcr gene and their correlation with the clinical course of Philadelphia-positive chronic myelogenous leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 485-490
Author(s):  
M Shtalrid ◽  
M Talpaz ◽  
R Kurzrock ◽  
H Kantarjian ◽  
J Trujillo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Chronic Myelogenous Leukemia ◽  
Clinical Course ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Blastic Crisis ◽  
Phase Duration ◽  
Dna Fragment

Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between chromosomes 9 and 22. The breakpoints on chromosome 22 are clustered within a 5.8-kilobase (kb) DNA fragment known as the breakpoint cluster region (bcr), which encodes part of a functionally active gene. We analyzed the bcr in DNAs from 108 consecutive, unselected Philadelphia chromosome-positive CML patients by Southern blot and determined five restriction enzyme fragments within which breaks occur on chromosome 22. The exact sublocalization was determined in the DNA of 100 patients. It was found to be within the 5.8-kb in 99 patients and outside the bcr in only one. Within the bcr, most of the breakpoints occurred in fragments 1, 2, and 3. Overall, laboratory and clinical features of CML did not correlate with specific breakpoint fragments, but chronic-phase duration was longer in patients with a breakpoint in fragment 2 of the bcr. Large 3′ bcr deletions were found in nine patients but did not influence clinical outcome. DNA from one of six patients analyzed both during chronic phase and blastic crisis showed an additional aberrant fragment, which suggested that a second abnormal clone developed in blastic crisis.

scholarly journals Coexistence of Recurrent Chromosomal Abnormalities and the Philadelphia Chromosome in Acute and Chronic Myeloid Leukemias: Report of Five Cases and Review of Literature

2020 ◽  
Author(s):  
Jinying Gong ◽  
Zhenhao Zhang ◽  
Wei Zhang ◽  
Huijun Wang ◽  
Xiaofang Feng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Myelogenous Leukemia ◽  
Trisomy 8 ◽  
Extra Copy ◽  
Genetic Abnormalities ◽  
Acute Myeloid

Abstract Progression of chronic myelogenous leukemia (CML) is frequently accompanied by cytogenetic evolution. Additional genetic abnormalities are seen in 10-20 % of CML cases at the time of diagnosis, and in 60–80 % of cases of advanced disease. Unbalanced chromosomal changes such as an extra copy of the Philadelphia chromosome (Ph), trisomy 8, and i(17)(q10) are common. Balanced chromosomal translocations, such as t(3;3), t(8;21), t(15;17), and inv(16) are typically found in acute myeloid leukemia, but rarely occur in CML. Translocations involving 11q23, t(8;21), and inv(16) are relatively common genetic abnormalities in acute leukemia, but are extremely rare in CML. In the literature to date, there are at least 76 Ph+ cases with t(3;21), 47 Ph+ cases with inv(16), 16 Ph+ cases with t(8;21), and 9 Ph+ cases with t(9;11). But most of what has been published is now over thirty years old, without the benefit of modern immunophenotyping to confirm diagnosis, and before the introduction of treatment regimes such as TKI. In this study, we explored the rare concomitant occurrence of coexistence current chromosomal translocation and t(9;22) in CML or acute myeloid leukemia (AML).

scholarly journals C-sis and C-abl expression in chronic myelogenous leukemia and other hematologic malignancies

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 839-841
Author(s):  
P Romero ◽  
M Blick ◽  
M Talpaz ◽  
E Murphy ◽  
J Hester ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosomal Rearrangements ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Aberrant Expression

Cellular oncogenes have been localized at the breakpoints of characteristic chromosomal rearrangements occurring in certain hematologic malignancies. This has been reported to result in aberrant expression of the involved oncogenes. Over 90% of chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation that brings c-abl from chromosome 9 to chromosome 22, and c-sis from chromosome 22 to chromosome 9. To investigate the possible role of these two oncogenes in the leukemic process, we studied their expression in a number of fresh samples obtained from patients with various forms of leukemia, by Northern blot analysis using c-onc probes. Seven of 24 samples obtained from patients with either CML or chronic myelomonocytic leukemia expressed a normal 4.0-kilobase (kb) c- sis transcript. C-sis expression was found only in the accelerated/blast phases but not in the chronic phase of CML. All of the CML Philadelphia chromosome-positive (Ph1+) samples expressed an aberrant 8-kb c-abl transcript. The expression of c-sis in

scholarly journals Identification of molecular variants of p210bcr-abl in chronic myelogenous leukemia

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 233-236
Author(s):  
R Kurzrock ◽  
WS Kloetzer ◽  
M Talpaz ◽  
M Blick ◽  
R Walters ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
K562 Cells ◽  
Protein Product ◽  
Myelogenous Leukemia ◽  
Kinase Assay ◽  
Molecular Variants ◽  
Immune Complex Kinase Assay ◽  
Hydrophilic Domain

The aberrant abl protein product of a chronic myelogenous leukemia (CML) blast crisis cell line (K562) and of five Philadelphia chromosome- positive CML patients in blast crisis were analyzed by an immune complex kinase assay using two antipeptide sera generated against the hydrophilic domain of v-abl and a region within the third exon of the breakpoint cluster region (bcr) respectively. Both the anti-abl and anti-bcr sera detected a 210 kd band in extracts derived from K562 cells and from two CML patients with myeloid blast crisis. p210 was detected by the anti-abl but not the anti-bcr sera in three CML patients with myeloid (one patient) and lymphoid (two patients) blast crisis, indicating the absence of bcr exon 3 in this protein. Southern blot analysis on DNA derived from one of the patients in the latter group was consistent with the break on chromosome 22 occurring 5′ to bcr exon 3. Our observations demonstrate that the Philadelphia translocation results in the generation of a chimeric bcr-abl protein with at least two molecular variants, both of which are enzymatically active as protein kinases.

scholarly journals C-sis and C-abl expression in chronic myelogenous leukemia and other hematologic malignancies

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 839-841 ◽  
Author(s):  
P Romero ◽  
M Blick ◽  
M Talpaz ◽  
E Murphy ◽  
J Hester ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosomal Rearrangements ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Aberrant Expression

Abstract Cellular oncogenes have been localized at the breakpoints of characteristic chromosomal rearrangements occurring in certain hematologic malignancies. This has been reported to result in aberrant expression of the involved oncogenes. Over 90% of chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation that brings c-abl from chromosome 9 to chromosome 22, and c-sis from chromosome 22 to chromosome 9. To investigate the possible role of these two oncogenes in the leukemic process, we studied their expression in a number of fresh samples obtained from patients with various forms of leukemia, by Northern blot analysis using c-onc probes. Seven of 24 samples obtained from patients with either CML or chronic myelomonocytic leukemia expressed a normal 4.0-kilobase (kb) c- sis transcript. C-sis expression was found only in the accelerated/blast phases but not in the chronic phase of CML. All of the CML Philadelphia chromosome-positive (Ph1+) samples expressed an aberrant 8-kb c-abl transcript. The expression of c-sis in

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