A recurrent splicing variant without c-ABL Exon 7 in Imatinib-resistant patients

Curvo, Raphael; Zalcberg, Ilana; Scholl, Vanesa; Pires, Virgínia; Moellmann-Coelho, Arthur; Moreira, Miguel A. M.

doi:10.1016/j.leukres.2007.04.018

Cited by 13 publications

(12 citation statements)

References 9 publications

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“…In addition, different deleted or inserted forms have been described recently and several studies focused on their incidence and putative deleterious potential. bcr-abl delexon7 was first described by Curvo et al (14) who found it in five resistant patients and hypothesized that it could be related to imatinib resistance. In a large cohort of resistant patients, Sherbenou et al reported 2 cases of this deletion among 101 samples.…”

Section: Discussionmentioning

confidence: 98%

“…To date, up to 100 point mutations have been described, 17 of them accounting for roughly 80% to 90% of cases (9,10). Recently, new kinds of mutations have been described, which do not correspond to a point mutation but to a large rearrangementlike in-frame deletions in exon 4 (11), insertion of 35 bp between exon 8 and exon 9 (12), insertion of 12 nucleotides in exon 5 (13), and complete deletion of exon 7 (14,15). It is to date generally assumed that these "new mutations" are related to a high-degree resistance level to imatinib.…”

Section: Introductionmentioning

confidence: 99%

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Exon 7 Deletion in the bcr-abl Gene Is Frequent in Chronic Myeloid Leukemia Patients and Is Not Correlated with Resistance against Imatinib

Gaillard

Arnould

Bravo

et al. 2010

Molecular Cancer Therapeutics

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Chronic myeloid leukemia (CML) patients treated with imatinib develop frequent resistance generally due to a point mutation. Recently, large rearrangements of abl sequence have also been described. In this study, we focused on the complete deletion of exon 7. We screened for bcr-abl delexon7 in 63 resistant patients by high-resolution melting (HRM) analysis and direct sequencing. Moreover, we analyzed expression of abl delexon7 and bcr-abl delexon7 in 17 CML patients at diagnosis, 32 patients at resistance, and 20 negative controls by quantitative PCR or fragment length analysis. bcr-abl delexon7 was detected on 34 (54%) among 63 resistant patients by HRM, showing an increase in the sensitivity of screening, because only 3.2% could be detected by direct sequencing. This deletion was not associated with a point mutation (P = 0.3362). In addition, abl delexon7 was found in all tested samples with the same pattern of expression, suggesting an alternative splicing mechanism. In the bcr-abl component, there was no statistical difference between CML patients at diagnosis and resistant patients (P = 0.2815) as regarding bcr-abl delexon7 proportion, thus arguing against involvement of deletion in resistance. Moreover, among two patients harboring bcr-abl delexon7 at diagnosis, one experienced a complete disappearance of this transcript, and the other decreased >75% at resistance. In conclusion, bcr-abl delexon7 is frequently observed in CML patients when using sensitive techniques. It seems to be the result of an alternative splicing mechanism and to be independent from the occurrence of resistance. Mol Cancer Ther; 9(11); 3083-9. ©2010 AACR.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Exon 7 Deletion in the bcr-abl Gene Is Frequent in Chronic Myeloid Leukemia Patients and Is Not Correlated with Resistance against Imatinib

Gaillard

Arnould

Bravo

et al. 2010

Molecular Cancer Therapeutics

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“…These mutations, clearly involved in IM resistance, were identified in some hematopoietic progenitors, whereas they were not detected in blood samples at the time of T315I identification. The rare deletion of exon 7 (Dexon7 detected in three colonies) leading to a premature stop codon and consequently to a truncated protein, and the 72 bp deletion of the 5 0 end of exon 7 (D363-386, found in two colonies), have also been reported in patients with IM-resistant CML [27,28]. Some mutations have only been characterized in in vitro experiments.…”

Section: Discussionmentioning

confidence: 99%

Extensive analysis of the T315I substitution and detection of additional ABL mutations in progenitors and primitive stem cell compartment in a patient with tyrosine kinase inhibitor-resistant chronic myeloid leukemia

Chomel

Sorel²,

Bonnet

et al. 2010

Leukemia & Lymphoma

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Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, resistance is occasionally observed, mainly due to mutations within the BCR-ABL kinase domain. The T315I substitution confers complete resistance to all TKIs commonly used in clinical practice. To date, the hierarchical level of stem cells in which this mutation initially appears has not been studied. The aim of this study was to evaluate the behavior of T315I mutated cells and to study the presence of potential additional mutations in progenitors and stem cells from a patient with CML. A comprehensive analysis of BCR-ABL(315I) mRNA expressing cells in mononuclear cells, in CD34+ cell populations, and in their primitive long-term culture-initiating cell (LTC-IC) derived progenitors was performed. We show that the T315I substitution arises in primitive Ph1 stem cells without altering their myeloid and erythroid terminal differentiation potential. Leukemic cells expressing a T315I mutated BCR-ABL display a progressive decline in LTC-IC assays as described for non-mutated CML cells at diagnosis. Finally, in our experiments, additional non-315 ABL mutations were identified in hematopoietic stem cell colonies. This observation is suggestive of genetic instability affecting CML progenitors.

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“…c.1086‐1270. This deletion was first described by Curvo et al3 in 2008, who suggested that this mutation appears as a result of alternative splicing and may be one of the causes of TKI resistance. However, Gaillard et al4 in 2010 showed that the frequency of deletion occurrence is not statistically different in the groups of drug‐resistant and sensitive patients.…”

Section: Discussionmentioning

confidence: 93%

BCR‐ABL exon 7 deletion and novel point mutation in patient with chronic myelogenous leukemia and TKI resistance

Абдуллаев

Nemchenko²,

Nesterova³

et al. 2018

Clinical Case Reports

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A recurrent splicing variant without c-ABL Exon 7 in Imatinib-resistant patients

Cited by 13 publications

References 9 publications

Exon 7 Deletion in the bcr-abl Gene Is Frequent in Chronic Myeloid Leukemia Patients and Is Not Correlated with Resistance against Imatinib

Exon 7 Deletion in the bcr-abl Gene Is Frequent in Chronic Myeloid Leukemia Patients and Is Not Correlated with Resistance against Imatinib

Extensive analysis of the T315I substitution and detection of additional ABL mutations in progenitors and primitive stem cell compartment in a patient with tyrosine kinase inhibitor-resistant chronic myeloid leukemia

BCR‐ABL exon 7 deletion and novel point mutation in patient with chronic myelogenous leukemia and TKI resistance

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