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Year : 2013  |  Volume : 9  |  Issue : 1  |  Page : 3-5

Breakpoint cluster region-c-abl oncogene 1, non-receptor tyrosine kinase signaling: Current patterns of the versatile regulator revisited

1 National Institute for Genomics and Advanced Biotechnology (NIGAB), NARC, Islamabad; Attaur Rahman School of Applied Biosciences (ASAB), National University of Science and Technology, Islamabad, Pakistan
2 National Institute for Genomics and Advanced Biotechnology (NIGAB), NARC, Islamabad, Pakistan
3 Attaur Rahman School of Applied Biosciences (ASAB), National University of Science and Technology, Islamabad, Pakistan
4 Punjab Medical College, Faisalabad, Pakistan
5 Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore, Lahore, Pakistan
6 Lab for Translational Oncology and Personalized Medicine, Rashid Latif Medical College (RLMC), Ferozepur Road, Lahore, Pakistan

Date of Web Publication10-Apr-2013

Correspondence Address:
Aamir Rana
National Institute for Genomics and Advanced Biotechnology (NIGAB), NARC, Islamabad, Atta ur Rahman School of Applied Biosciences (ASAB), National University of Science and Technology, Islamabad
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.110338

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 > Abstract 

Increasing sophisticated information suggests that cancer cells express constitutively active oncogenic kinases such as breakpoint cluster region- c-abl oncogene 1, non-receptor tyrosine kinase (BCR-ABL1) that promote carcinogenesis independent of extrinsic growth factors. It is a well-established fact that through the aberrant activation of BCR-ABL1 signal transduction cascade, the perception of cellular growth signals becomes disconnected from the processes promoting cell growth, and this underlies the pathophysiology of leukemia. In this particular review we discuss the oncogenes and tumor suppressors comprising the regulatory network upstream and downstream of BCR-ABL1 and dismantle how derailed BCR-ABL1 signaling provides cell a selective growth advantage. Besides, we discuss why activation of BCR-ABL1, as an outcome of distinct oncogenic events, results in miscellaneous clinical outcomes, and how the intricacy of the BCR-ABL1 signaling network might dictate therapeutic approaches. In this review, our current comprehension of BCR-ABL1 signaling will be summarized.

Keywords: Breakpoint cluster region-c-abl oncogene 1, non-receptor tyrosine kinase, Imatinib, Chronic myeloid leukemia

How to cite this article:
Rana A, Ali GM, Ali S, Khan A, Sabiha B, Malik S, Riaz AM, Farooqi AA. Breakpoint cluster region-c-abl oncogene 1, non-receptor tyrosine kinase signaling: Current patterns of the versatile regulator revisited . J Can Res Ther 2013;9:3-5

How to cite this URL:
Rana A, Ali GM, Ali S, Khan A, Sabiha B, Malik S, Riaz AM, Farooqi AA. Breakpoint cluster region-c-abl oncogene 1, non-receptor tyrosine kinase signaling: Current patterns of the versatile regulator revisited . J Can Res Ther [serial online] 2013 [cited 2020 Sep 19];9:3-5. Available from: http://www.cancerjournal.net/text.asp?2013/9/1/3/110338

 > Introduction Top

Substantial information suggests that autophagy and apoptosis may be triggered by common upstream signals, and occasionally these result in combined autophagy and apoptosis. However, often, cell switches between the two responses in a mutually exclusive manner. Detailed mechanistic insights unravel the fact that apoptotic and autophagic response nano-machineries share common pathways that either link or polarize the cellular responses.

 > BCR-ABL1 Signaling Top

BCR (breakpoint cluster region) being a component of the mammalian endosomal sorting complex required for transport (ESCRT), it plays a significant role in the cellular trafficking of growth factor receptors. [1] BCR-ABL1 stimulates Jab-1 coactivator of AP-1 transcription factor, which mediates degradation of the tumor suppressor p53 and p27, thereof BCR-ABL1 functions as a tumor promoter in different types of human cancer expression via the cooperative interaction of β-catenin and STAT1 (signal transducer and activator of transcription 1) in leukemic cells. [2] BCR-ABL1 elicits antiapoptotic effects in BCR-expressing cells. ABL1-kinase inhibitor treatments or depletion of BCR-ABL1 induces RAB45, now called as RASEF (RAS and EF-hand domain containing) messenger ribonucleic acid (RNA) and its ultimate protein expression, which leads to apoptosis via mitochondrial membrane production reduction as well as p38 activation in BCR-ABL1 progenitor cells of chronic myeloid leukemia (CML) patients. [3] Ubiquitin-cycle inhibition represents an effective and novel approach for blocking BCR-ABL1 kinase signaling and reduction of Mcl-1 levels to engage CML cell apoptosis. This approach might prove to be a therapeutic option for CML patients resistant to kinase inhibitor. [4] Since Sphingosine kinase-1 SK-1/S1P/S1P2 signaling regulates the stability of BCR-ABL1 via PP2A modulation in CML patients, so inhibition of SK-1/S1P2 axis corresponds to a novel approach for targeting wild-type- or mutant-BCR-ABL1, thereby overcoming drug resistance. [5]

Chronic myeloid leukemia-chronic phase (CML-CP) cells contain plentiful deoxyribonucleic acid (DNA) double-strand breaks whose unfaithful repair contributes toward the chromosomal instability and disease progression to blast phase (CML-BP). BCR-ABL1 kinase-mediated RAD51 (pY315) recombinase promotes unfaithful homeologous recombination repair (HomeoRR) in leukemic cells. [6] Disruption of the Fanconi anemia FA/BRCA pathway in BCR-ABL1 cells suggests this defective pathway to play a crucial role in the genomic instability of CML by the cooccurrence of DNA repair deficiencies and centrosomal amplification. [7] In contrast, a cytosine-to-thymine mutation at ABL1 gene position 944 was identified, which takes part in threonine-to-isoleucine amino acid substitution at amino acid position 315 in ATP-binding domain of BCR-ABL1oncoprotein. [8],[9],[10] It has been dogged, on the basis of the crystal structure of ABL1 kinase domain, that Threonine 315 is among those amino acids which make hydrogen bonds with Gleevec by providing an oxygen atom. Moreover, it holds an extra hydrocarbon group in the side chain, which fallouts in steric hindrance to Gleevec. [11] Thus uncontrolled inauguration of signaling cascades restrains the vital role in the CML progression.

 > Autophagy Top

BCR-ABL1 transcriptionally up-regulates ATF5 expression through PI3K/AKT/FOXO4 signaling and that ATF5 further stimulates the transcription of mammalian target of rapamycin (mTOR; also called mechanistic target of rapamycin), a potent negative-regulator of autophagy. Imatinib mesylate, the BCR-ABL1 inhibitor, induces both autophagy and apoptosis, and the resultant autophagy in turn modulates the imatinib efficiency of killing BCR-ABL1-transformed cells. [12] Autophagy is the lysosomal breakdown of cellular components. Imatinib induces autophagy in CML cells through BECLIN-1 and ATG5 genes over-expression. Autophagy comes up to be a major factor involved in the cell death induced by imatinib. [13] Low-BCR-ABL1-expressing cells engage in a delayed nonapoptotic cell death. Imatinib treatment induces both autophagy and apoptosis in all BCR-ABL1-expressing cells leading to a rapid population recovery. Combination regime for incorporating such agents that disrupt the autophagy induced by imatinib, leaving behind its apoptotic activity alone, would remain focused and may improve the CML treatment response. [14] Autophagy mitigates cellular stress, and the cells expressing the oncogenic kinase BCR-ABL1 peculiarly depend on autophagy for cell survival and leukemogenesis in a way that autophagy suppresses a stress response that otherwise leads to the phoshoylation of p53 and up-regulation of p21 and the pro-apoptotic Bcl-2 family protein Puma. [15] The mTOR pathway induced by BCR-ABL1 promotes leukemogenesis and mitogenic responses. Autophagy is a limiting factor for the apoptosis induction during dual mTORC2-mTORC1 targeting in some BCR-ABL1-expressing cells types and have brought into knowledge the approach of combinatorial catalytic mTOR inhibitors with autophagy inhibitors for the treatment of refractory leukemias. [16]

 > Intracellular Localization Top

Cytoplasmic BCR-ABL1 causes oncogenesis/proliferation while the nuclear BCR-ABL1 induces apoptosis. Altering the ectopically expressed BCR-ABL1 location kills leukemic cells. Multiple nuclear localization signals (NLSs), which overcome BCR-ABL1 binding to actin, would thus be required for its driving toward nucleus and eliciting of ultimate apoptosis and leukemic treatment. [17] BV02, a nonpeptidic inhibitor of 14-3-3 (suppressor of antiproliferative signals), could be considered as a treatment option for CML and for those CML patients with imatinib mesylate resistance as a consequence of BCR-ABL1 point mutations. [18] BCR-ABL1 possesses the signals for nuclear import and export, but it remains localized only in the cytoplasm for activating mitogenic and antiapoptotic pathways. Thereof BCR-ABL1 nuclear entrapment is another therapy that may selectively kill chronic myelogenous leukemic cells. [19] The BCR-ABL1-activated tyrosine kinase resides in the cytoplasm. Imatinib acts to reactivate the NLS function of BCR-ABL1 in a kinase-defective BCR-ABL1 mutant. Elucidation of the kinase domain structural interactions, the NLS region, and the FABD (F-actin binding domain) provides insights into the next-generation BCR-ABL1 inhibitors designing for CML treatment. [20] BCR-ABL1 high-level oncoproteins are required for the suppression of C/EBPalpha-driven myeloid differentiation while being dependent on MAPK-hnRNP-E2. [21] The nucleocytoplasmic trafficking of those mRNAs that encode proteins influencing the normal and BCR-ABL1-transformed myeloid progenitors phenotype depends on the shuttling activity of hnRNP A1. [22]

 > Therapeutic Interventions Top

The pattern of genomic rearrangement is paramount to demarcate the key players mediating oncogenesis. Imatinibmesylate (Gleevec) is a functional therapy against Philadelphia chromosome positive leukemia but resistance widens in all phases of the disease. BCR-ABL1 point mutations and other alterations diminish the kinase inhibitory activity of imatinib mesylate. Adaphostin, an analog of the tyrphostin AG957 and WP1130 (tyrosine kinase inhibitors), revealed that it induced rapid down-regulation of BCR-ABL1 without affecting BCR or ABL1 but misplaced its effectiveness in the existence of mutations in BCR-ABL1. [23],[24] Point mutations C944T and T932C have been detected in ABL1 gene, which take part in complete/partial imatinib resistance. The restless transgenic activity of mutated BCR-ABL1, resistant to imatinib, includes a vital role in the CML progression. [9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] Recently it has been reported that rapamycin-treated CML cell line (K562) highlighted a decreased mTOR, 4E-BP1, and p70S6K phosphorylation. Treatment with higher dose (20nmol/l or more) of rapamycin increases apoptotic cells, decreases bcl-2 expression, and activates caspase-3. Therefore,rapamycin could be a reasonable therapeutic aspect for the treatment of CML. [26]

 > Acknowledgment Top

The corresponding author would like to sincerely thank Dr. Sobia Manzoor (Attaur Rahman School of Applied Biosciences (ASAB), National University of Science and Technology, Islamabad, Pakistan) for her helpful suggestions during the structuring of the review.

 > References Top

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2.Yang KT, Wang MC, Chen JY, Hsu MC, Hung WC. Bcr-Abl oncogene stimulates Jab1 expression via cooperative interaction of β-catenin and STAT1 in chronic myeloid leukemia cells. J Cell Physiol 2011;226:2849-56.  Back to cited text no. 2
3.Nakamura S, Takemura T, Tan L, Nagata Y, Yokota D, Hirano I, et al. Small GT Pase RAB 45-mediated p38 activation in apoptosis of chronic myeloid leukemia progenitor cells. Carcinogenesis 2011;321:1758-72.  Back to cited text no. 3
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8.Roche-Lestienne C, Preudhomme C. Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment. Semin Hematol 2003;40:80-2.  Back to cited text no. 8
9.Iqbal Z, Siddiqui RT, Qureshi JA.Two different point mutations in ABL gene ATP-binding domain conferring primary imatinib resistance in a chronic myeloid leukemia (CML) patient: A case report. Biol Proced Online 2004;6:144-8.  Back to cited text no. 9
10.Rana A, Bhatti S, Ali GM, Ali S, Rehman N, Shah SH, et al. Authentication of fusion genes in chronic myeloid leukemia. IJBMBR 2011;2:128-30.  Back to cited text no. 10
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15.Altman BJ, Jacobs SR, Mason EF, Michalek RD, MacIntyre AN, Coloff JL, et al. Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis. Oncogene 2011;30:1855-67.  Back to cited text no. 15
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18.Mancini M, Corradi V, Petta S, Barbieri E, Manetti F, Botta M, et al. A new nonpeptidic inhibitor of 14-3-3 induces apoptotic cell death in chronic myeloid leukemia sensitive or resistant to imatinib. J Pharmacol Exp Ther 2011;336:596-604.  Back to cited text no. 18
19.Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 2011;7:228-34.  Back to cited text no. 19
20.Preyer M, Vigneri P, Wang JY. Interplay between kinase domain autophosphorylation and F-actin binding domain in regulating imatinib sensitivity and nuclear import of BCR-ABL. PLoS One 2011;6:e17020.  Back to cited text no. 20
21.Chang JS, Santhanam R, Trotta R, Neviani P, Eiring AM, Briercheck E, et al. High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation. Blood 2007;110:994-1003.  Back to cited text no. 21
22.Iervolino A, Santilli G, Trotta R, Guerzoni C, Cesi V, Bergamaschi A, et al. hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis. Mol Cell Biol 2002;22:2255-66.  Back to cited text no. 22
23.Sawyers CL, McLaughlin J, Witte ON. Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene. J Exp Med 1997;181:307-13.  Back to cited text no. 23
24.Mow BM, Chandra J, Svingen PA, Hallgren CG, Weisberg E, Kottke TJ, et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro. Blood 2002;99:664-71.  Back to cited text no. 24
25.Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Laï JL, Philippe N, Facon T, et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 2002;100:1014-8.  Back to cited text no. 25
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