Deletion of BCR region 3′ in chronic myelogenous leukemia

González, Fernando; Anguita, Eduardo; Mora, Asunción; Asenjo, Susana; López, Ignacio F.; Polo, Marta; Villegas, Ana

doi:10.1016/s0165-4608(01)00469-1

Cited by 12 publications

(7 citation statements)

References 30 publications

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Section: The Anatomy Of Derivative Chromosome 9 Deletions In CMLmentioning

confidence: 99%

“…Although small deletions (approximately 10 kb) of chromosome 22 sequences next to the translocation breakpoint had previously been demonstrated by Southern blotting, these were thought to be of no pathophysiologic importance. [45][46][47] By contrast the FISH data suggested the existence of substantial deletions spanning at least several hundred kilobases (Figure 3).In order to delineate the size of the deletions FISH mapping was performed in the 16 patients with deletions originally described by Sinclair et al 44 The results highlighted 3 main features of the deletions. First, the deletions were adjacent to and usually spanned the translocation breakpoint of the derivative chromosome 9.…”

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confidence: 98%

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Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia

Huntly¹,

Bench²,

Green³

2003

Blood

114

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Chronic myeloid leukemia (CML) is characterized by formation of a BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Recently the development of new fluorescence insitu hybridization (FISH) techniques has allowed identification of unexpected deletions of the reciprocal translocation product, the derivative chromosome 9, in 10% to 15% of patients with CML. These deletions are large, span the translocation breakpoint, and occur at the same time as the Ph translocation. Such deletions therefore give rise to previously unsuspected molecular heterogeneity from the very beginning of this disease, and there is mounting evidence for similar deletions associated with other translocations. Several studies have demonstrated that CML patients who carry derivative chromosome 9 deletions exhibit a more rapid progression to blast crisis and a shorter survival. Deletion status is independent of, and more powerful than, the Sokal and Hasford/European prognostic scoring systems. The poor prognosis associated with deletions is seen in patients treated with hydroxyurea or interferon, and preliminary evidence suggests that patients with deletions may also have a worse outcome than nondeleted patients following stem cell transplantation or treatment with imatinib. Poor outcome cannot be attributed to loss of the reciprocal ABL-BCR fusion gene expression alone, and is likely to reflect loss of one or more critical genes within the deleted region. The molecular heterogeneity associated with the Philadelphia translocation provides a new paradigm with potential relevance to all malignancies associated with reciprocal chromosomal translocations and/or fusion gene formation. IntroductionChronic myeloid leukemia (CML) is a clonal hematologic malignancy that arises in the stem cell compartment. [1][2][3] Its molecular hallmark is the BCR-ABL fusion gene, 4,5 which usually occurs as the result of the Philadelphia (Ph) translocation involving the long arms of chromosomes 9 and 22. 6 The chimeric BCR-ABL gene encodes a constitutively activated protein tyrosine kinase, which leads to the activation of multiple signaling pathways, with profound effects on cell cycle, adhesion, and apoptosis. 2,3 In murine transgenic and retroviral transduction models, expression of BCR-ABL has been shown to be both sufficient for initiation and necessary for maintenance of a leukemic phenotype. [7][8][9][10][11][12][13][14] The natural history of CML follows a biphasic pattern with an initial chronic phase, which is often asymptomatic. This is inevitably followed by progression of the disease through an ill-defined stage termed accelerated phase to the terminal blast crisis. During chronic phase, the myeloid compartment is expanded but the cells retain their capacity to differentiate and function normally, and drug treatment is usually effective. By contrast, blast crisis is characterized by loss of differentiation capacity together with refractoriness to therapy and is associated with the acquisit...

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Section: The Anatomy Of Derivative Chromosome 9 Deletions In CMLmentioning

confidence: 99%

mentioning

confidence: 98%

Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia

Huntly¹,

Bench²,

Green³

2003

Blood

114

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“…Considering the results of CCyR and MMR of patients with reciprocal t(9;22), there is no difference between the patients with and without deletion of BCR region. González et al [ 25 ] reported a lack of difference between the group with the deletion and the group without deletion, which supports the hypothesis that the ABL1-BCR fusion gene containing the major BCR (M-BCR) sequence 3′ to the breakpoint does not play the main role in the leukemogenesis of CML.…”

Section: Discussionmentioning

confidence: 81%

The incidence of atypical patterns ofBCR-ABL1rearrangement and molecular-cytogenetic response to tyrosine kinase inhibitor therapy in newly diagnosed cases with chronic myeloid leukemia (CML)

et al. 2018

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BackgroundTo analyze the frequency of atypical fluorescence in situ hybridization signal patterns and estimate the complete cytogenetic response (CCyR) and major molecular response (MMR) during 12 months of tyrosine kinase inhibitor therapy in patients with newly diagnosed chronic myeloid leukemia.MethodsThe study included bone marrow and peripheral blood samples from 122 patients with newly diagnosed chronic myeloid leukemia. Detection of the breakpoint cluster region—Abelson fusion gene (BCR-ABL1) was performed using fluorescence in situ hybridization with a dual-color dual-fusion translocation probe, and MMR analysis was performed using the real-time quantitative polymerase chain reaction method.ResultsVariant translocation was determined in 10 samples and a deletion on the derivative chromosome 9 (del/der(9)) was found in 20 samples. The rates of CCyR and MMR were similar between patients with reciprocal translocation, variant translocation, deletion of derivative BCR, or ABL1-BCR fusion gene. The Kaplan-Meier test did not show any significant differences in the rates of CCyR and MMR among those groups of patients.ConclusionThe frequencies of variant translocation and del/der(9) in the present study agree with the results of other studies performed worldwide. No differences were observed in the rates of CCyR and MMR between patients with atypical patterns and reciprocal translocation.

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“…30,31,32 Cerca de 9% a 33% dos casos de LMC têm deleção der(9q), fato que confere sobrevida significativamente mais curta que aqueles sem tal deleção. [33][34][35][36][37][38] Estudo realizado em 120 pacientes com LMC Ph+/BCR/ABL+ atendidos no ambulatório de Leucemias da Disciplina de Hematologia e Hemoterapia da Unifesp revelou a presença de deleção no der(9q) ou del 5' ABL em 15% dos casos. Esses pacientes apresentaram sobrevida global (27 versus 61 meses, p=0,02) e duração da fase crônica (17 versus 56 meses, p=0,02) significativamente menores que os pacientes sem a deleção.…”

Section: Citogenética Molecular: Hibridação In Situ Por Fluorescênciaunclassified

Análise citogenética e FISH no monitoramento da LMC em tratamento com inibidores da tirosino quinase

Chauffaille¹

2008

Rev. Bras. Hematol. Hemoter.

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Análise citogenética e FISH no monitoramento da LMC em tratamento com inibidores da tirosino quinase Cytogenetics and FISH monitoring CML during tyrosine kinase inhibitors treatment Maria de Lourdes L. F. Chauffaille O monitoramento de tratamento com inibidor da tirosinoquinase (TK) tem sido feito com os objetivos de avaliar o sucesso da terapia e de definircondutas específicas nos casos nos quais não se obtem a remissão da LMC; naqueles em que ocorre a perda da remissão previamente alcançada, na eventualidade ou não de suspensão da medicação; quando há a evolução clonal a despeito da terapia ou o aparecimento de alterações clonais nas células Philadelphia (Ph)-negativas. Recomenda-se a avaliação citogenética aos três ou seis meses de instituição da terapêutica e, a partir daí, a cada seis meses até a remissão citogenética completa. Uma vez alcançada a remissão citogenética, o monitoramento passa a ser porPCR quantitativo em tempo real (PCR em tempo real, porém o cariótipo deve ser realizado a cada ano para a detecção de perda de resposta, alterações clonais em células Ph-negativas ou evolução clonal. Com efeito, só o cariótipo pode monitorar a aquisição de alteração clonal associada à progressão da doença. No presente manuscrito são também discutidos: Ph-variantes, deleção no derivado 9q e aparecimento de alterações clonais nas células Ph-negativas, situações menos freqüentes, mas que merecem monitoração mais amiúde. Rev. bras.

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Deletion of BCR region 3′ in chronic myelogenous leukemia

Cited by 12 publications

References 30 publications

Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia

Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia

The incidence of atypical patterns ofBCR-ABL1rearrangement and molecular-cytogenetic response to tyrosine kinase inhibitor therapy in newly diagnosed cases with chronic myeloid leukemia (CML)

Análise citogenética e FISH no monitoramento da LMC em tratamento com inibidores da tirosino quinase

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