BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients—Frequency and clinical outcome

Elias, Marjanu Hikmah; Baba, Abdul Aziz; Husin, Azlan; Hassan, Rosline; Sim, Goh Ai; Padmini, Menon; Fadilah, S A W; Ankathil, Ravindran

doi:10.1016/j.leukres.2013.12.025

Cited by 48 publications

(42 citation statements)

References 23 publications

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“…31 Reported literature suggests that different muatations instigate varying levels of response alteration against Imatinib therapy in CML patients. 32 So, the detection of K D mutations before any change in cytogenetic or molecular response might be a potent indicator for changing therapy. 33 Our patients were evaluated as Imatinib sensitive by physicians at the time of mutation analysis.…”

Section: Discussionmentioning

confidence: 99%

Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression

Akram

Iqbal

Akhtar

et al. 2017

Cancer Biology & Therapy

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BCR-ABL kinase domain (K D ) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-K D mutations in chronic phase (n D 41), late chronic phase (n D 33) and accelerated phase (n D 16) imatinib responders. Direct sequencing analysis was used for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which 8 (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-K D . Occurrence of mutations was found associated with elevated platelet count (p D 0.037) and patients of male sex (p D 0.049). The median overall survival and event free survival of CML patients (n D 90) was 6.98 and 5.8 y respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-K D mutation screening in late chronic phase CML patients for improved clinical management of disease.

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Section: Discussionmentioning

confidence: 99%

Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression

Akram

Iqbal

Akhtar

et al. 2017

Cancer Biology & Therapy

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“…Although Imatinib provides highly effective therapeutic outcome to treat Ph positive CML patients, about 30 % of patients become Imatinib resistant due to acquire mutations of ABL tyrosine kinase domain (TKD) leading to disease relapse. Therefore, mutation analysis of ABL TKD is critical for the mutation screening before the treatment as well as during Imatinib treatment (Branford et al, 2003;Hughes et al, 2009;Kim et al, 2009;Wongboonma et al, 2012;Elias et al, 2014). In summary, the combination of comprehensive techniques including complete cytogenetic study, FISH, PCR-based technology is essential for the achievement of the best therapeutic outcome in treatments of Ph positive CML and ALL.…”

Section: Discussionmentioning

confidence: 99%

Multiplex RT-PCR Assay for Detection of Common Fusion Transcripts in Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Cases

Limsuwanachot

Siriboonpiputtana²,

Karntisawiwat³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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“…3 This resistance is caused by drug efflux mechanism, so that imatinib could not reach its target or mutation on BCR-ABL kinase domain occur and causing the target to be insensitive. 3,32 To resolve this resistence, new medicines which are second generation tirosin kinase inhibitor, are developed, dasatinib and nilotinib. 3,33 In vitro, dasatinib has 350 times more potential compare to imatinib, while nilotinib 50 times.…”

Section: Treatment With Tkimentioning

confidence: 99%

Fusion Gene BCR-Abl : From Etiopathogenesis to the Management of Chronic Myeloid Leukemia

Sholikah

2017

JKKI

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Review ArticleSholikah, Fusion gene bcr-abl... 29Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm. CML is relative frequent disorder. Most of CML patients have Philadelphia chromosome (Ph),which is derived from a reciprocal translocation between chromosome 9 and 22, t(9;22)(q34;ql1), generating the BCRABLfusion gene. In general, there are 3 breakpoint cluster regions in BCR gene : mayor(M-bcr), minor (m-bcr) and micro (µ-bcr). The BCR-ABL gene encodes proteins that vary in size depending on the breakpoint in the BCR gene. However, these proteins share a high tyrosine kinase activity. In the absence of activating stimuli, BCR-ABL tyrosine kinase able to transferphosphate from ATP (autophosphorilation) to tyrosine residues on various substrates in the cell. It actives intracelluler signaling pathways. These pathways cause increase proliferation or decrease apoptosis and differentiation of a hematopoietic stem cell; and defect in adherence of myeloid progenitors to marrow stroma resulting in CML. These discoveries determined that BCR-ABL fusion gene is critical event in etiopathogenesis of CML and a ideal target for therapy. Therapy of CML patients with BCR-ABL fusion gene-positif is by block autophosphorilation mechanism by Tyrosine Kinase Inhibitor (TKI), example imatinib. Molecular method to detect BCR-ABL transcript is necessary for monitoring response to TKI in CML pateints. Chronic Myeloid Leukemia (CML) merupakan keganasan myeloproliferatif yang relatif sering ditemukan. Sebagian besar pasien CML mempunyai kromosom Philadelphia, yaitu kromosom yang berasal dari hasil translokasi resiprokal antara kromosom 9 dan 22, t(9;22)(q34;q11) sehingga membentuk gen fusi BCR-ABL. Secara umum, terdapat 3 tipe breakpoint cluster region gen BCR-ABL yaitu mayor (M-bcr), minor (m-bcr) dan mikro (µ-bcr). Gen fusi BCR-ABL mengkode protein dengan ukuran yang berbeda-beda tergantung tipe breakpointnya. Namun, semua protein tersebut mempunyai aktivitas tirosin kinase yang tinggi. Aktivitas tirosin kinase BCR-ABL dapat mengambil gugus fosfat dari ATP meskipun pada kondisi tidak ada stimulus (autofosforilasi

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BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients—Frequency and clinical outcome

Cited by 48 publications

References 23 publications

Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression

Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression

Multiplex RT-PCR Assay for Detection of Common Fusion Transcripts in Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Cases

Fusion Gene BCR-Abl : From Etiopathogenesis to the Management of Chronic Myeloid Leukemia

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