A polymorphism in exon b2 of the major breakpoint cluster region (M‐bcr) identified in chronic myeloid leukaemia patients

Meissner, Rosely de Vasconcellos; Dias, Paula Menna Barreto; Covas, Dimas Tadeu; Job, Fani; Leite, Márcia; Nardi, Nance Beyer

doi:10.1046/j.1365-2141.1998.00945.x

Cited by 20 publications

(18 citation statements)

References 9 publications

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“…[6][7][8][9][10][11][12] However, to our knowledge, only two studies have addressed the effect of transcript type on the clinical outcome of patients treated with imatinib. One small study of 22 patients in Brazil with variable disease status found a significant difference in response to treatment at 6 months (p=0.0347), with e13a2-expressing patients responding better than those expressing e14a2.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

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Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Lucas¹,

Harris²,

Giannoudis³

et al. 2009

Haematologica

105

116

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BackgroundChronic myeloid leukemia is characterized by a reciprocal translocation between chromosomes 9 and 22, creating the fusion gene BCR-ABL. The clinical significance of the type of BCR-ABL transcript in newly diagnosed patients in chronic phase treated with imatinib 400 mg from initial diagnosis remains unknown. Design and MethodsWe analyzed the clinical outcome of 78 newly diagnosed chronic phase patients, aged 16 or over, treated with imatinib 400 mg. Of these, 71 expressed either e13a2 or e14a2 transcripts. BCR-ABL transcripts were assayed by quantitative real-time polymerase chain reaction. ResultsAfter 12 months of treatment, 54% of the e14a2 patients had achieved a complete cytogenetic response, compared to 25% of the e13a2 patients (p=0.01). Kaplan-Meier analysis of the time to achieve complete cytogenetic response revealed that e14a2 patients had more rapid response rates, compared to e13a2 patients (p=0.006). e14a2 patients had a higher event-free survival rate in the first 12 months of treatment, although overall survival did not differ significantly between the patients with the two types of transcript. Human organic cation transporter protein 1 mRNA levels did not differ between the patients with the two types of transcript. The pre-treatment pCrKL/CrKL ratio (a surrogate marker of BCR-ABL tyrosine kinase activity) was higher in patients with e13a2 transcripts than in those with e14a2 (p=0.017). ConclusionsPatients expressing the e14a2 transcript type have a higher rate and more rapid complete cytogenetic responses than e13a2-expressing patients, which may be due to higher BCR-ABL tyrosine kinase activity. Knowledge of the transcript type may yield additional prognostic information, although this requires testing on larger datasets.Key words: chronic myeloid leukemia, BCR-ABL fusion transcript, imatinib. Haematologica 2009;94:1362-1367. doi:10.3324/haematol.2009 This is an open-access paper.

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…[6][7][8][9][10][11][12] In the imatinib era one small study of 22 patients in different phases of disease suggested that patients with the e13a2 BCR-ABL transcript may be more sensitive to imatinib treatment; 13 while a larger study indicated that patients with e14a2 have a better molecular response to imatinib.…”

Section: Introductionmentioning

confidence: 99%

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Lucas¹,

Harris²,

Giannoudis³

et al. 2009

Haematologica

105

116

View full text Add to dashboard Cite

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“…15 The latter distribution is similar to the pattern observed in adult Philadelphia-positive acute lymphoblastic leukemia (Ph 1 ALL) with M-BCR rearrangement. 16,17 These differences in the genomic landscape may contribute to the more aggressive clinical characteristics in pediatric CML compared with adult CML.…”

Section: Introductionmentioning

confidence: 99%

“…Both RNA variants can occur either alone or simultaneously depending on alternative splicing of the e14a2 transcript, which is influenced by intronic and exonic DNA polymorphisms. [16][17][18] There are conflicting reports on the influence of these transcript phenotypes on hematologic findings at diagnosis. The majority of, 13 but not all, 12 studies in adults with CML showed that high platelet counts are observed more often in patients expressing the e14a2 transcript.…”

Section: Introductionmentioning

confidence: 99%

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach

Hijiya

Schultz

Metzler

et al. 2016

Blood

167

176

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Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.

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“…The BCR intronic polymorphism, however, occurs at the invariant A of a sequence that is the best match to the poorly conserved branchpoint. It has been proposed that the change results in reduced efficiency of splicing of intron 13 of BCR and BCR-ABL allele [5][6][7] and use of the acceptor site at the end of intron 14, leading to coexpression of both the transcripts.…”

Section: Introductionmentioning

confidence: 99%

Molecular profiling of chronic myeloid leukemia in eastern India

et al. 2006

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Molecular breakpoint of the BCR-ABL fusion gene has been characterized for 122 chronic myeloid leukemia patients. Out of 122 cases, 33 b2a2, 69 b3a2, 2 e1a2, and 2 e19a2 cases have been detected. Six coexpressed both b2a2 and b3a2 transcripts. All the coexpressing samples had an A>G polymorphism at the putative splice branchpoint in intron 13. The T>C polymorphism in exon 13, reported to be linked to coexpression, was not present in all the coexpressing patients. No correlation of transcript type with platelet count was detected. Those expressing b2a2 transcript were diagnosed at relatively younger age and with higher white blood cell count, in agreement with other reports. However, the correlation was not statistically significant. Am. J. Hematol. 81:845-849, 2006. V V C 2006 Wiley-Liss, Inc.

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A polymorphism in exon b2 of the major breakpoint cluster region (M‐bcr) identified in chronic myeloid leukaemia patients

Cited by 20 publications

References 9 publications

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach

Molecular profiling of chronic myeloid leukemia in eastern India

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