scholarly journals Highly precise breakpoint detection of chromosome balanced translocation in a Chronic Myelogenous Leukemia patient

2021 ◽  
Author(s):  
Chuanchun Yang ◽  
Xiaoli Cui ◽  
Lei Xu ◽  
Qian Zhang ◽  
Shanmei Tang ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Chromosome Breakage ◽  
Small Region ◽  
Chromosome Translocation ◽  
Myelogenous Leukemia ◽  
Balanced Translocation ◽  
Base Level

Abstract Chronic Myelogenous Leukemia (CML) has a special phenomenon of chromosome translocation, which is called Philadelphia chromosome translocation. However, the detailed connection of this structure is troublesome and expensive to be identified. Low-coverage whole genome sequencing (LCWGS) could not only detect the chromosomal translocation which does not be known in advance, but also provide the breakpoint candidate small region (with an accuracy of ±200 bases). Importantly, the sequencing cost of LCWGS is about US$300. Then, with the Sanger DNA sequencing, the precise breakpoint can be determined at a single base level. In our project, with LCWGS, BCR and ABL1 are successfully identified and were disrupted at chr22:23,632,356 and chr9:133,590,450, respectively. Due to the reconnection after chromosome breakage, classical fusion gene (BCR-ABL1) was found in bone marrow and peripheral blood. The precise breakpoints were helpful to study the pathogenic mechanism of CML and could better guide the classification of CML subtypes. This LCWGS method is universal and can be used to detect all diseases related to chromosome variation, such as solid tumors, liquid tumors and birth defects.

Identification of human chronic myelogenous leukemia progenitor cells with hemangioblastic characteristics

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2733-2740 ◽  
Author(s):  
Baijun Fang ◽  
Chunmei Zheng ◽  
Lianming Liao ◽  
Qin Han ◽  
Zhao Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Blood Cells ◽  
Fusion Gene ◽  
Fetal Liver ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Leukemic Cells

AbstractOverwhelming evidence from leukemia research has shown that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation. There are rare stem cells within the leukemic population that possess extensive proliferation and self-renewal capacity not found in the majority of the leukemic cells. These leukemic stem cells are necessary and sufficient to maintain the leukemia. Interestingly, the BCR/ABL fusion gene, which is present in chronic myelogenous leukemia (CML), was also detected in the endothelial cells of patients with CML, suggesting that CML might originate from hemangioblastic progenitor cells that can give rise to both blood cells and endothelial cells. Here we isolated fetal liver kinase-1–positive (Flk1+) cells carrying the BCR/ABL fusion gene from the bone marrow of 17 Philadelphia chromosome–positive (Ph+) patients with CML and found that these cells could differentiate into malignant blood cells and phenotypically defined endothelial cells at the single-cell level. These findings provide direct evidence for the first time that rearrangement of the BCR/ABL gene might happen at or even before the level of hemangioblastic progenitor cells, thus resulting in detection of the BCR/ABL fusion gene in both blood and endothelial cells.

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

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2162-2170 ◽  
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.

scholarly journals A novel BCR-ABL fusion gene (e6a2) in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2236-2240 ◽  
Author(s):  
A Hochhaus ◽  
A Reiter ◽  
H Skladny ◽  
JV Melo ◽  
C Sick ◽  
...  
Keyword(s):  
Southern Blot ◽  
Chronic Myelogenous Leukemia ◽  
Rare Variants ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Rt Pcr ◽  
Novel Variant ◽  
Polymerase Chain

A novel variant of the chimeric BCR-ABL mRNA transcript was detected in a patient with Philadelphia chromosome-negative (Ph-) chronic myelogenous leukemia (CML) by multiplex reverse-transcription polymerase chain reaction (RT-PCR). Sequence analysis of the fusion region of the amplified cDNA fragment showed an in-frame joining of exon e6 of the BCR gene and exon a2 of the ABL gene, giving rise to an e6a2 BCR-ABL transcript. This finding was confirmed by Southern blot analysis using a specific probe corresponding to intron 6 of the BCR gene, whereas conventional Southern blot for rearrangement of the major breakpoint cluster region (M-bcr) was negative. Western blot studies detected a BCR-ABL protein slightly larger than p185 BCR-ABL. Metaphase fluorescence in situ hybridization showed an insertion of ABL material into the BCR region without reciprocal BCR translocation. The findings in this case show that atypical BCR-ABL transcripts are detectable even in Ph- CML patients without M-bcr-rearrangements. Multiplex PCR using primers that allow for amplification of all known BCR-ABL transcripts is an appropriate method to exclude these rare variants.

scholarly journals Chromosomal breakpoints within the first intron of the ABL gene are nonrandom in patients with chronic myelogenous leukemia

Blood ◽  
1990 ◽  
Vol 76 (3) ◽  
pp. 597-601 ◽  
Author(s):  
XY Jiang ◽  
JM Trujillo ◽  
JC Liang
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Bone Marrow Cells ◽  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
First Intron ◽  
Chromosomal Breakpoints ◽  
Translocation Breakpoints ◽  
Specific Sequences

Abstract Bone marrow cells from 37 patients with chronic myelogenous leukemia (CML), who had the characteristic Philadelphia chromosome in their leukemic cells, were examined for ABL gene rearrangement by pulsed- field gel electrophoresis. By using several probes from the ABL gene, we found that in 33 of 37 (89%) patients studied, the translocation breakpoints in ABL fell within the 175-kilobase (kb) intron between exons 1b and 1a. Furthermore, breakpoints in this intron clustered in three regions, approximately 30 +/- 5, 100 +/- 13, and 135 +/- 8 kb downstream from exon 1b. These findings suggest that there may be specific sequences in this intron that facilitate the processes of chromosomal translocation.

A Unique, Complex Variant Philadelphia Chromosome Translocation in a Patient With Typical Chronic Myelogenous Leukemia

2001 ◽  
Vol 125 (3) ◽  
pp. 437-439
Author(s):  
Raida Oudat ◽  
Zebunnisa Khan ◽  
Armand B. Glassman
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Chromosome Translocation ◽  
Chromosome 9 ◽  
Myelogenous Leukemia ◽  
Chromosome 11 ◽  
Ph Chromosome ◽  
Conventional Cytogenetics

Abstract The Philadelphia (Ph) chromosome [der(22) t(9;22)(q34;q11)] is the characteristic chromosomal abnormality found in chronic myelogenous leukemia (CML). This chromosome has been reported in patients with other chromosomal abnormalities. In this study, we describe a patient with hematologically typical chronic-phase CML with an unusual and complex translocation involving chromosomes 9, 11, and 22. These complex translocations were identified by G-banded conventional cytogenetics and confirmed by fluorescence in situ hybridization (FISH) using whole chromosome painting probes (wcp). To the best of our knowledge, these are unique translocations involving the short and the long arms of chromosome 9 in 4 different translocations with the short arm of chromosome 11 and the long arm of chromosome 22.

scholarly journals Chromosomal breakpoints within the first intron of the ABL gene are nonrandom in patients with chronic myelogenous leukemia

Blood ◽  
1990 ◽  
Vol 76 (3) ◽  
pp. 597-601 ◽  
Author(s):  
XY Jiang ◽  
JM Trujillo ◽  
JC Liang
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Bone Marrow Cells ◽  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
First Intron ◽  
Chromosomal Breakpoints ◽  
Translocation Breakpoints ◽  
Specific Sequences

Bone marrow cells from 37 patients with chronic myelogenous leukemia (CML), who had the characteristic Philadelphia chromosome in their leukemic cells, were examined for ABL gene rearrangement by pulsed- field gel electrophoresis. By using several probes from the ABL gene, we found that in 33 of 37 (89%) patients studied, the translocation breakpoints in ABL fell within the 175-kilobase (kb) intron between exons 1b and 1a. Furthermore, breakpoints in this intron clustered in three regions, approximately 30 +/- 5, 100 +/- 13, and 135 +/- 8 kb downstream from exon 1b. These findings suggest that there may be specific sequences in this intron that facilitate the processes of chromosomal translocation.

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

1983 ◽  
Vol 1 (11) ◽  
pp. 669-676 ◽  
Author(s):  
K Jain ◽  
Z Arlin ◽  
R Mertelsmann ◽  
T Gee ◽  
S Kempin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Leukocyte Antigen ◽  
Terminal Transferase

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3547-3553 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
Susan O'Brien ◽  
Francis J. Giles ◽  
Maher Albitar ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Response Rate ◽  
Philadelphia Chromosome ◽  
Response To Therapy ◽  
Myelogenous Leukemia ◽  
Control Group ◽  
Blast Phase ◽  
Molecular Abnormalities ◽  
Philadelphia Chromosome Positive

Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph+ below 35%], and 4 minor [Ph+, 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P = .001), longer median survival (7 versus 4 months, P = .04), and lower 4-week induction mortality (4% versus 15%, P = .07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.

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