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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 1  |  Page : 6-10

BCR-ABL1 in leukemia: Disguise master outplays riding shotgun


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 Lab for Translational Oncology and Personalized Medicine, Rashid Latif Medical College (RLMC), 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
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.110339

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 > Abstract 

Leukemia is a many-sided molecular disorder that arises because of over expression of oncogenes, suppression of tumor suppressor genes, and chromosomal translocations. These chromosomal rearrangements are nonetheless among the many determinants that underlie transformation of cells from normal to a cancerous phenotype and predispose cells to refractoriness against interventions by reduced drug influx and substantial drug efflux. This review unfolds current understanding of BCR-ABL1 (break point cluster region-c-abl oncogene 1, non-receptor tyrosine kinase) signaling with a focus on apoptotic suppressive mechanisms and alternative approaches to chronic myeloid leukemia therapy.

Keywords: BCR-ABL1, imatinib, chronic myeloid leukemia


How to cite this article:
Rana A, Ali GM, Ali S, Khan A, Mansoor S, Malik S, Farooqi AA. BCR-ABL1 in leukemia: Disguise master outplays riding shotgun. J Can Res Ther 2013;9:6-10

How to cite this URL:
Rana A, Ali GM, Ali S, Khan A, Mansoor S, Malik S, Farooqi AA. BCR-ABL1 in leukemia: Disguise master outplays riding shotgun. J Can Res Ther [serial online] 2013 [cited 2019 Nov 19];9:6-10. Available from: http://www.cancerjournal.net/text.asp?2013/9/1/6/110339


 > Introduction Top


Chronic myeloid leukemia (CML) is a myeloproliferative disorder that appears after dysregulated clonal expansion and demarcation of totipotent hematopoietic stem cells. [1],[2] CML is a biphasic or triphasic disease initiating with a chronic phase and then progressing through an uneven accelerated phase into an acute phase (blastic phase) resembling an acute myeloid or lymphoid leukemia. [3] Almost all patients hold a specific translocation t(9;22) (q34;q11.2) and derivative der-(22)of the Philadelphia chromosome (Ph), which results in the juxtaposition of the deoxyribonucleic acid (DNA) sequence from the BCR-ABL1 genes and encodes dysregulated tyrosine kinase thatis essential and adequate for leukemogenesis. [4] Although Ph is thought to be the preliminary event in CML, gaining additional cytogenetic abnormalities is likely responsible for disease progression. [5] Fusion of BCR sequences to ABL1 during translocation associated with CML boosts the tyrosine kinase activity of ABL1, and brings new regulatory domains/motifs to ABL1, such as the growth factor receptor-bound protein 2 (GRB2) SH2-binding site. Depending on the exact breakpoints in the translocation and RNA splicing, different types of BCR-ABL1 proteins with different molecular weights (p185 BCR-ABL1, p210 BCR-ABL1, and p230 BCR-ABL1) can be generated in patients. [6],[7] Two isoforms of ABL1 (Human types 1a and 1b) are produced by alternative splicing of the first exon; one of them (1b) contains a myristoylation modification site (Myr). Despite the alternatively spliced sequences, in the amino terminal, half of ABL1 contains tandem SH3, SH2, and the tyrosine-kinase domains. These domains can amass into an auto-inhibitory structure, in which the SH3 and SH2 domains function as a 'clamp' that holds the kinase in the 'off' state 119, 120. [8] Since the first imatinib-resistant cases, point mutations in the kinase domain (KD) of BCR-ABL1 were identified that could worsen or even totally abrogate imatinib binding. [9],[10] Over the past decade, rigorous efforts have been made in the characterization of the biologic and clinical consequence of these mutations on the one hand and in the development of novel inhibitors retaining efficacy against as many BCR-ABL1 mutant forms as possible on the other hand. Clinical experience with dasatinib and nilotinib, the second-generation tyrosine kinase inhibitors (TKIs), having predictable market approval so far has confirmed that exact, much narrower spectra of mutations retain insensitivity to these agents and these spectra are non overlapping, T315I being the unique exception. [5] In spite of the encouraging results with TKIs in chronic phase, secondary resistance caused by BCR-ABL1 mutations as well as primary resistant disease (accelerated phase CML or blast crisis) hampers the response to antileukemic treatment. [11] This study reviews the key points involved in disease progression, signal transduction cascades, and stimuli leading to chromosomal rearrangements.

BCR-ABL1 and drug resistance: Is it the time to move back to square one?

Imatinib has awestruck the physicians, clinicians, patients, and researchers by its high efficacy intherapy for BCR-ABL1-positive CML patients. [12] As it impedes the oncogenic activity of BCR-ABL1 oncoprotein by binding to its ATP-binding site in kinase domain, it has fewer side effects than interferon and is thus welltolerated. [13] Imatinib binds to some amino acids in ATP-binding domain by making hydrogen bonds. [9] It was found that some mutations in ABL1 gene ATP-binding domain direct to conformational alteration in BCR-ABL1 oncoprotein, thus resulting in impairment of imatinib binding and leading to clinical resistance. [14] Some mutations ground complete imatinib resistance as they completely stop the imatinib binding to its target while other mutations only affect this binding partially, leading to only temperate resistance to this drug. [15],[16] A cytosine-to-thymine mutation at ABL1 gene position 944 was confirmed, which causes threonine-to-isoleucine amino acid substitution at amino acid position 315 in ATP-binding domain of BCR-ABL1 oncoprotein. [17],[18] It has been determined, on the basis of crystal structure of ABL1 kinase domain, that threonine 315 is among those amino acids which create hydrogen bonds with imatinib by providing an oxygen atom. When isoleucine takes the place of threonine as a result of C944T mutation, it does not provide oxygen atom for binding. Moreover, it contains an extra hydrocarbon group in the side chain, which fallouts in steric hindrance to imatinib [Figure 1]. [19]
Figure 1: (a) The kinase domain of BCR-ABL1 oncoprotein in salmon color with imatinib (cyan) is shown, (b) The THR residue (yellow) at 315 interacts with imatinib through a hydrogen bond (black dashes), (c) Mutant T315I contains an ILE (white) with an extra carbon that creates steric hindrance against imatinib binding

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Recentdocumentation revealed that CML stem cells are not dependent on BCR-ABL1 kinase activity for their survival and that dasatinib effectively suppressed the fusion proteins carrying F359I mutation. [20],[21] Additionally, it has been demonstrated that tyrosine kinase inhibitor-mediated inhibition of dendritic cells function is triggered by up-regulation of the immune inhibitory molecule osteoactivin. [22] It is becoming progressively prominent that nilotinib and dasatinib have differential activity profiles. While drawing a parallel between these nilotinib and dasatinib, findings indicated that Lyn played a dominant role in survival of the nilotinib-resistant cell line. In contrast, dasatinib induced the apoptosis of nilotinib-resistant cells and suppressed Lyn kinase activity. [23] Confluence of information suggested that leukemic cells harboring BCR-ABL1 (T315I) mutant were highly resistant to imatinib, nilotinib, and dasatinib, and was frequently detected in relapsed patients. This mutation regulated switch control pocket that was believed to be involved in conformational regulation of the kinase domain. To overcome the resistance generated by the cells harboring this mutant fusion protein, DCC-2036 (an ABL1 switch control inhibitor) was designed, that attached well with switch control pocket involved in conformational regulation of the kinase domain. [24] Furthermore, noteworthy is that activation of STAT3 is essential not only for survival of CML cells but also for its protection against nilotinib. Consistent with the same concept, inhibition of BCR-ABL1 and JAK activity was a successful strategy to potentiate their elimination. [25] Moreover, cytokines are also suggested to be implicated in abrogating efficacy of TKIs in BCR-ABL1-positive cells. However, omacetaxine repressed common β-subunit c of the cytokine-receptors (cCRβc) in primary CML CD34+ progenitor cells, thus suggesting that a multipronged approach leads to better clinical management of leukemia. [26] Analogously, omacetaxine had suppressive effects in BCR-ABL1-expressing myelogenous and lymphoid cell lines and mouse models of CML and B-cell acute lymphoblastic leukemia (B-ALL) induced by wild-type BCR-ABL1 or T315I mutant-BCR-ABL1. [27] Preferential activity of OMA (omacetaxine) on the T315I-mutated cells has recently been documented by Nicolini et al.[28]

BCR-ABL1 crosstalk with other transduction cascades

It is a well knownthat BCR-ABL1 harboring leukemic cells are resistant to multiple drugs, irradiation by modulation of DNA repair mechanisms, cell cycle checkpoints, and Bcl-2 protein family members. [29],[30] Intriguingly, BCR-ABL1 triggered cellular proliferation in the absence of growth factors, and concurrently protected them from apoptosis. [31] BCR-ABL1 tyrosine kinase activity direct the activation of several signal transduction pathways that are also exploited by hematopoietic growth factors, including steel factor thrombopoietin, interleukin-3, and granulocyte/macrophage-colony stimulating factor. [32] Adaphostin, an analog of the tyrphostin AG957 and WP1130 (tyrosine kinase inhibitors), induces rapid down-regulation of BCR-ABL1 without affecting BCR or ABL1, however efficacy was severely hampered in the presence of mutations in BCR-ABL1. [33]

ABL1 is a protein kinase involved in the phosphorylation of various downstream molecules, but myristoylation in the hydrophobic region of the protein inactivates it by auto inhibition. Contrarily, fusion of BCR and ABL1 enhances the activity of ABL1. ABL1 activity is restored by the fusion of BCR with ABL1 and theresulting protein triggers activation of wide-ranging downstream substrates. [34] It is well acknowledged that BCR-ABL1 activates various signaling pathways, some of which may be crucial for its leukemogenic activity. The Ras, [35] PI3-K-Akt, [36],[37] JAK-STAT, [38] and NF-κB [39] signaling pathways are among those activated by BCR-ABL1. In accordance with the aptitude of BCR-ABL1 to substitute for the cytokines requirement, many of these pathways are also activated by hematopoietic cytokines upon binding to their respective cytokine receptors. Imperative motif in the BCR region of BCR-ABL1 is the GRB2-binding site. GRB2 binds SOS, a guanine-nucleotide exchanger of RAS and the scaffolding adapter GRB2-associated binding protein 2 (GAB2) formation of this complex direct the activation of RAS and recruitment of SHP2 and phosphatidylinositol 3-kinase (PI3K). [36] BCR-ABL1 plays a crucial role in enhancing expression and kinase activity of MEK kinase 1 (MEKK1), which acts upstream of the c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK), and NF-kB signaling pathways. [40] Stimulation of Jab-1 co-activator of AP-1 transcription factor by BCR-ABL1 mediates degradation of the tumor suppressor p53 and p27, therefore BCR-ABL1 functions as a tumor promoter in different types of human cancer expression via the cooperative interaction of β-catenin and STAT1 in leukemic cells. [41] The mTOR pathway induced by BCR-ABL1 promotes leukemogenesis and mitogenic responses with the up-regulation of FoxO subclass of forkhead transcription factors (FoxO1, FoxO3a, and FoxO4). [42] Autophagy is a restrictive factor for 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. [43] Increased BCR-ABL1 expression is linked with enhanced expression of antiapoptotic proteins, Bcl-XL and Mcl-1, possibly related to increased activation of STAT5 and MAPK in these cells. [44] The agitated activation of MYC via MAPK-dependent regulation of HNRPK translation regulatory activity holds significant impact in leukemogenesis. [7] The oncoprotein BCR-ABL1 inhibits the activation of CK-2 [45] and ICSBP, which confer resistance to programmed cell death. [46] Tumor suppressor genes have been shown to be inactivated or down-regulated by BCR-ABL1 in CML, including PP2A, p53, RB, [47] and PTEN. [48] PTENand p53 are simultaneously down-regulated in BCR-ABL1-expressing cells suggesting that the PTEN down-regulation by BCR-ABL1 may be mediated by P53 as PTEN transcription is regulated by p53. [49],[50] BCR-ABL1 oncoprotein-expressing cells are associated with a relative increase of intracellular reactive oxygen species (ROS) and the aberrant activation of β-catenin, which is thought to play a role in transformation. [51]

Leukemic cells display dysregulated drug retention

It has currently been shown that amantadine and prazosin enhanced the cytotoxicity of TKIs, imatinib, nilotinib, and dasatinib. This was due to release of intracellular calcium from the endoplasmic reticulum (ER), with noticeable changes in mitochondrial calcium and alterations in mitochondrial membrane permeability, resulting in caspase-mediated apoptosis. [52] Laboratory investigations showed that efflux transporters MDR1, MRP1, and ABCG2 were present on CML CD34+ cells. However, neither suppression of efflux transporter activity potentiated the effect of nilotinib on apoptosis nor suppression of human organic cation transporter 1 (hOCT1) attenuated cellular uptake of drug. [53] On the contrary, reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. [54] It was observed that the intracellular uptake and retention (IUR) of imatinib, OCT-1 activity, and OCT-1 mRNA expression was significantly lowered in CML CD34 + cells compared with mature CD34- cells. [55] Much has been added to the information of the existing pool of transporter proteins that are involved in the extrusion of therapeutic drugs. In line with this concept, data indicated that nilotinib could reverse ABCB1- and ABCG2-mediated MDR by blocking the efflux function of these transporters. [56] Furthermore, various documentations indicated that dasatinib and imatinib were transported from the basal to the apical layers, indicating that they were transported by ABCB1, which was confirmed using the ABCB1 inhibitor PSC833. Compared with imatinib, dasatinib achieved superior intracellular levels and BCR-ABL1 repression in leukemic cells that displayed low or blocked hOCT1. [57]


 > Conclusion Top


Genome-wide screening is believed to speed up the development of personalized medicine by identifying and outlining new associations between genomic variants and drug responses. Although inhibitors directed against the BCR-ABL1, such as imatinib, lead to clinical remission in the early stage of the disease, still most patients with advanced disease develop drug refractoriness connected with mutations in the ABL1 kinase domain.


 > Acknowledgment Top


The corresponding author sincerely thanks Dr. Sobia Manzoor, Dr. Attya Bhatti, Dr. Hajra Sadia and Dr. Sheeba Murad Maal (Atta urRahman School of Applied Biosciences (ASAB), National University of Science and Technology, Islamabad, Pakistan) for their helpful suggestions during the structuring of the review.

 
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