BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia

Salesse, Stéphanie; Verfaillie, Catherine M.

doi:10.1038/sj.onc.1206082

Cited by 123 publications

(71 citation statements)

References 196 publications

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“…1 Preclinical studies and clinical trials showed that imatinib exhibited a remarkable single-agent activity against BCR-ABL-expressing cells with acceptable toxicity in vitro and in vivo. 1,2 BCR-ABL tyrosine kinase activates several signaling pathways such as the Ras/mitogenactivated protein kinase, [2][3][4] signal transducer and activator of transcription 5, 2,4 and phosphatidylinositol 3 kinase/Akt pathways 2,4 ; enhances nuclear factor B (NF-B) activity 5 ; upregulates the level of Bcl-X L 5,6 ; and suppresses the mitochondrial apoptotic pathway. 5,7 Imatinib counteracts BCR-ABL tyrosine kinase and induces apoptosis in BCR-ABL-positive cells [8][9][10] in a caspase-dependent fashion.…”

Section: Introductionmentioning

confidence: 99%

A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

Okada

Adachi

Imai

et al. 2004

Blood

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Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL-positive cells in a caspasedependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate-induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate-treated BCR-ABL-positive human leukemic cells. Moreover, zVAD-fmk-preincubated, imatinib mesylate-treated cells exhibited a necrosislike morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2. IntroductionImatinib mesylate (imatinib, Gleevec) was developed as a potent and specific inhibitor of ABL tyrosine kinase. 1 Preclinical studies and clinical trials showed that imatinib exhibited a remarkable single-agent activity against BCR-ABL-expressing cells with acceptable toxicity in vitro and in vivo. 1,2 BCR-ABL tyrosine kinase activates several signaling pathways such as the Ras/mitogenactivated protein kinase, 2-4 signal transducer and activator of transcription 5, 2,4 and phosphatidylinositol 3 kinase/Akt pathways 2,4 ; enhances nuclear factor B (NF-B) activity 5 ; upregulates the level of 6 ; and suppresses the mitochondrial apoptotic pathway. 5,7 Imatinib counteracts BCR-ABL tyrosine kinase and induces apoptosis in BCR-ABL-positive cells [8][9][10] in a caspase-dependent fashion. 11,12 Recently, however, it has been revealed that responses to imatinib are not necessarily remarkable or durable in some patients with BCR-ABL-positive leukemia, [13][14][15][16][17][18][19][20][21][22] and thus an increasing number of studies have searched for a novel therapy targeting the BCR-ABL-induced signaling pathways. 5 Cell death is generally classified into 2 categories, apoptosis 23,24 and necrosis. Apoptosis is a well-documented active programmed cell death (PCD) in which the activation of caspases plays a central role. 25 In contrast, necrosis has been conceived as a passive cell death without established regulatory mechanisms. However, it has recently been reported that necrosis-like cell death may be re...

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Section: Introductionmentioning

confidence: 99%

A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

Okada

Adachi

Imai

et al. 2004

Blood

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“…28 Intracellular signaling pathway activated by BCR-ABL include RAS, PI3K, and STAT pathway. 25,28 Ras pathway would activate when BCR-ABL interact with adaptor protein like Grb2, Shc, Sos and Dok. Activated Ras would bind GTP.…”

Section: Molecular Pathogenesismentioning

confidence: 99%

“…BCR protein domains include oligomerization domain and phoposerin/ treonin rich SH2 binding domain. 25 Tirosin kinase ABL domain contributes in the activity of kinase which worked by transfering phosphate group of ATP to tirosin residue of various protein substrates, thus activating various intracellular pathway. This activity is strictly regulated intra cells.…”

Section: Molecular Pathogenesismentioning

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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“…As a result, the chimeric tyrosine kinase oncoprotein Bcr-Abl is expressed (Ben-Neriah et al, 1986). Unlike c-Abl that shuttles between the nucleus and the cytoplasm and whose kinase activity is finely tuned, Bcr-Abl is cytoplasmic and its kinase activity is increased and deregulated (Salesse & Verfaillie, 2002). Through phosphorylation of different substrates, Bcr-Abl activates different signal transduction pathways that participate in the control of cellular proliferation, differentiation, migration, adhesion and survival (Afar et al, 1994;Andreu et al, 2005;Bedi et al, 1994; …”

Section: Bcr-abl and Its Control Of The Cell Cycle And Apoptosismentioning

confidence: 99%

The Proteasome as a Therapeutic Target in Chronic Myeloid Leukemia

Pérez‐Roger¹,

Albero²

2011

Myeloid Leukemia - Basic Mechanisms of Leukemogenesis

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BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia

Cited by 123 publications

References 196 publications

A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

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

The Proteasome as a Therapeutic Target in Chronic Myeloid Leukemia

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