Consistent Loss of Heterozygosity at 14q32 in Lymphoid Blast Crisis of Chronic Myeloid Leukemia

Sercan, Hakki Ogun; Sercan, Zeynep; Kızıldağ, Sefa; Ündar, Bülent; Soydan, Saliha; Sakızlı, Meral

doi:10.3109/10428190009065838

Cited by 13 publications

(8 citation statements)

References 19 publications

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“…The first role is stimulation of signaling pathways, which contribute to malignant transformation, including proliferation in the absence of growth factors, protection from apoptosis in the absence of external survival factors and invasion (Kolibaba and Druker, 1997;Liu et al, 2000;Cross and Reiter, 2002;Arlinghaus and Sun, 2004). The second role of FTKs in hematological malignancies is the modulation of responses to DNA damage, rendering cells resistant to genotoxic therapies and causing genetic instability (Alimena et al, 1987;Kelman et al, 1989;Laneuville et al, 1992;Bedi et al, 1995;Nishii et al, 1996;Amarante-Mendes et al, 1998;Dubrez et al, 1998;Villamor et al, 1999;Honda et al, 2000;Salloukh and Laneuville, 2000;Sercan et al, 2000;Aoki et al, 2001;Greenland et al, 2001;Slupianek et al, 2001).…”

Section: Consequences Of Ftks Expressionmentioning

confidence: 99%

Fusion tyrosine kinases: a result and cause of genomic instability

Penserga

Skórski

2006

Oncogene

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Section: Consequences Of Ftks Expressionmentioning

confidence: 99%

Fusion tyrosine kinases: a result and cause of genomic instability

Penserga

Skórski

2006

Oncogene

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“…The salient features of these investigations seem to be that TP53 mutations are associated with myeloid BC and homozygous deletions of CDKN2A with lymphoid BC [103, 111, 112, 113, 117], LOH at 4p, 7p, 9p, 14q32, 18q, and 19p are more common in lymphoid BC [122, 189], and the methylation status of the major breakpoint cluster region of the BCR gene may differ between myeloid and lymphoid BC [190]. …”

Section: Secondary Aberrations In Relation To Morphologymentioning

confidence: 99%

Cytogenetic and Molecular Genetic Evolution of Chronic Myeloid Leukemia

2002

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Chronic myeloid leukemia (CML) is genetically characterized by the presence of the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22 called the Philadelphia (Ph) chromosome. In 2–10% of the cases, this chimeric gene is generated by variant rearrangements, involving 9q34, 22q11, and one or several other genomic regions. All chromosomes have been described as participating in these variants, but there is a marked breakpoint clustering to chromosome bands 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13. Despite their genetically complex nature, available data indicate that variant rearrangements do not confer any specific phenotypic or prognostic impact as compared to CML with a standard Ph chromosome. In most instances, the t(9;22), or a variant thereof, is the sole chromosomal anomaly during the chronic phase (CP) of the disease, whereas additional genetic changes are demonstrable in 60–80% of cases in blast crisis (BC). The secondary chromosomal aberrations are clearly nonrandom, with the most common chromosomal abnormalities being +8 (34% of cases with additional changes), +Ph (30%), i(17q) (20%), +19 (13%), –Y (8% of males), +21 (7%), +17 (5%), and monosomy 7 (5%). We suggest that all these aberrations, occurring in >5% of CML with secondary changes, should be denoted major route abnormalities. Chromosome segments often involved in structural rearrangements include 1q, 3q21, 3q26, 7p, 9p, 11q23, 12p13, 13q11–14, 17p11, 17q10, 21q22, and 22q10. No clear-cut differences as regards type and prevalence of additional aberrations seem to exist between CML with standard t(9;22) and CML with variants, except for slightly lower frequencies of the most common changes in the latter group. The temporal order of the secondary changes varies, but the preferred pathway appears to start with i(17q), followed by +8 and +Ph, and then +19. Molecular genetic abnormalities preceding, or occurring during, BC include overexpression of the BCR/ABL transcript, upregulation of the EVI1 gene, increased telomerase activity, and mutations of the tumor suppressor genes RB1, TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in relation to treatment given during CP. For example, +8 is more common after busulfan than hydroxyurea therapy, and the secondary changes seen after interferon-alpha treatment or bone marrow transplantation are often unusual, seemingly random, and occasionally transient. Apart from the strong phenotypic impact of addition of acute myeloid leukemia/myelodysplasia-associated translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and t(15;17)(q22;q12–21), in CML BC, only a few significant differences between myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being more frequent in lymphoid BC. The prognostic significance of the secondary genetic changes is not uniform, althoug...

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“…[1][2][3] The second role of BCR/ABL in hematological malignancies, is that it can modulate response to DNA damage rendering cells resistant to genotoxic therapies [4][5][6][7][8][9][10][11] and causing genomic instability. [12][13][14][15][16][17][18] Accumulation of mutations is believed to be responsible for transition of a relatively benign CML chronic phase (CML-CP) to the aggressive blast crisis (CML-BC), and the resistance to imatinib mesylate (IM). 19,20 BCR/ABL stimulates numerous signaling molecules including Ras, PI-3k and STAT5, which are essential not only for leukemogenesis [21][22][23][24][25][26][27][28][29][30] but also for resistance to apoptosis induced by DNA damage.…”

Section: Introductionmentioning

confidence: 99%

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

Nieborowska‐Skorska

Stokłosa²,

Datta³

et al. 2006

Cell Cycle

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BCR/ABL-positive leukemia cells accumulated more replication-dependent DNA doublestrand breaks (DSBs) than normal counterparts after treatment with cisplatin and mitomycin C (MMC, as assessed by pulse field gel electrophoresis (PFGE) and neutral comet assay. In addition, leukemia cells could repair these lesions more efficiently than normal cells and eventually survive genotoxic treatment. Elevated levels of drug-induced DSBs in leukemia cells were associated with higher activity of ATR kinase, and enhanced phosphorylation of histone H2AX on serine 139 (γ-H2AX). γ-H2AX eventually started to disappear in BCR/ABL cells, while continued to increase in parental cells. In addition, the expression and ATR-mediated phosphorylation of Chk1 kinase on serine 345 were often more abundant in BCR/ ABL-positive leukemia cells than normal counterparts after genotoxic treatment. Inhibition of ATR kinase by caffeine but not Chk1 kinase by indolocarbazole inhibitor, SB218078 sensitized BCR/ABL leukemia cells to MMC in a short-term survival assay. Nevertheless, both caffeine and SB218078 enhanced the genotoxic effect of MMC in a long-term clonogenic assay. This effect was associated with the abrogation of transient accumulation of leukemia cells in S and G 2 /M cell cycle phases after drug treatment. In conclusion, ATR -Chk1 axis was strongly activated in BCR/ABL-positive cells and contributed to the resistance to DNA cross-linking agents causing numerous replication-dependent DSBs.

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Consistent Loss of Heterozygosity at 14q32 in Lymphoid Blast Crisis of Chronic Myeloid Leukemia

Cited by 13 publications

References 19 publications

Fusion tyrosine kinases: a result and cause of genomic instability

Fusion tyrosine kinases: a result and cause of genomic instability

Cytogenetic and Molecular Genetic Evolution of Chronic Myeloid Leukemia

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

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