Disease relevance of BCR

• BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive human leukemias [1].
• BCR-ABL is a chimeric oncogene implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias [2].
• The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of human pre-B cells [3].
• The BCR/ABL oncogene encodes an activated tyrosine kinase that causes human chronic myelogenous leukemia [4].
• Four of 13 BCR/ABL transgenic founders developed a chronic MPD, but only one progressed to blast crisis [5].

Psychiatry related information on BCR

• The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies [6].
• Assuming that imatinib could be included in pretransplantation conditioning therapies, we tested whether combinations of imatinib and gamma-irradiation or alkylating agents such as busulfan or treosulfan would display synergistic activity in BCR-ABL-positive chronic myelogenous leukaemia BV173 and EM-3 cell lines [7].
• The association is stronger for BCR enlargement than for VBR enlargement, suggesting that selective caudate region atrophy is associated with HIV dementia [8].
• We found significantly elevated levels of CML in CSF of AD patients and of pentosidine in CSF of patients suffering from vascular dementia when compared to controls [9].
• The age-dependent accumulation of CML in lens protein indicates that products of both glycation and oxidation accumulate in the lens with age, while the constant rate of accumulation of CML in lens with age argues against an age-dependent decline in free radical defense mechanisms in this tissue [10].

High impact information on BCR

• The BCR-ABL story: bench to bedside and back [11].
• More sophisticated analysis of clinical and cytogenetic parameters will lead to identification of additional subtypes of hematologic neoplasms such as t(15;17) APL or Ph1-positive CML [12].
• A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL [13].
• Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL [14].

Chemical compound and disease context of BCR

• To gain insight into factors that influence the action of a prototypical targeted drug, we studied the action of imatinib (STI-571, Gleevec) against murine cells and leukemias expressing BCR-ABL, an imatinib target and the initiating oncogene for human chronic myelogenous leukemia (CML) [15].
• In a murine bone marrow transduction/transplantation model, the three forms of BCR/ABL were equally potent in the induction of a chronic myeloid leukemia (CML)-like myeloproliferative syndrome in recipient mice when 5-fluorouracil (5-FU)-treated donors were used [16].
• A novel, phosphotyrosine-independent binding interaction between BCR, the Philadelphia chromosome breakpoint cluster region gene product, and the SH2 domain of its translocation partner c-ABL has recently been reported [17].
• Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitor, exhibits greater potency than imatinib mesylate (IM) and inhibits the majority of kinase mutations in IM-resistant chronic myeloid leukemia (CML) [18].
• Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction) [19].

Biological context of BCR

• The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy [11].
• Comparing genome-wide gene expression profiles of BCR-ABL1+ pre-B ALL and normal bone marrow pre-B cells by serial analysis of gene expression, many genes involved in pre-B cell receptor signaling are silenced in the leukemia cells [3].
• One of the important contributions of BCR to transformation is believed to be dimerization or oligomerization of ABL, thereby activating ABL tyrosine kinase activity [4].
• Introduction of the BCR/ABL oncogene into this cell line resulted in factor-independent proliferation and constitutive phosphorylation of p95Vav [20].
• The N-terminal sequence of the protein is derived from the BCR gene on chromosome 22 [21].

Anatomical context of BCR

• The BCR-ABL (Y177F) mutant is unable to transform primary bone marrow cultures and is impaired in its ability to transform Rat1 fibroblasts [1].
• We conclude that inhibition of BCR-ABL1 reconstitutes selection for leukemia cells expressing a functional (pre-) B cell receptor [3].
• We used this methodology to follow changes in tyrosine phosphorylation patterns that occur over time during either the activation of human T cells or the inhibition of the oncogenic BCR-ABL fusion product in chronic myelogenous leukemia cells in response to treatment with STI571 (Gleevec) [22].
• Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model [23].
• Both processes are closely associated with the t(9;22) chromosomal translocation that creates the BCR/ABL fusion gene in hematopoietic stem cells (HSCs) and their progeny [5].

Associations of BCR with chemical compounds

• BCR first exon sequences specifically activate the tyrosine kinase and transforming potential of BCR-ABL [2].
• Phosphoserine/phosphothreonine but not phosphotyrosine residues on BCR are required for interaction with the ABL SH2 domain [2].
• The BCR gene encodes a novel serine/threonine kinase activity within a single exon [24].
• A region containing paired cysteine residues within the 426 amino acids encoded by the first exon of BCR is essential for its novel phosphotransferase activity, which overlaps with the strong SH2-binding regions [24].
• Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation [1].

Physical interactions of BCR

• An immune complex kinase assay showed that the 230-kDa BCR/ABL protein ahd autophosphorylation activity [25].
• Although the biological significance of the binding remains to be uncovered, BCR binds to the XPB/p62 complex [26].
• The amino terminal CRKL SH3 domain binds directly to a proline-rich region in the C-terminus of BCR-ABL [27].
• These data provide evidence that BCR couples the cytoplasmic protein-tyrosine kinase and RAS signaling pathways [28].
• SHP-1 remained attached to the BCR in subgroup Ia, but not in subgroup Ib, where signal transduction was associated with an excess of truncated CD79b [29].

Enzymatic interactions of BCR

• The binding appeared to be required for XPB to be tyrosine-phosphorylated by BCR-ABL [30].
• The SH2-SH3 domain-containing adaptor protein CRKL is the predominant tyrosine phosphorylated protein in chronic myelogenous leukemia (CML) neutrophils and BCR-ABL-expressing cell lines [27].
• Because recent evidence has clearly implicated both PI(3,4, 5)P3 and PI(3,4)P2 in growth factor-mediated signaling, our finding that both SHIP1 and SHIP2 are constitutively tyrosine phosphorylated in CML primary hematopoietic progenitor cells may thus have important implications in p210(bcr/abl)-mediated myeloid expansion [31].
• We have examined the ability of additional SH2 domains to bind phosphotyrosine-free BCR and compared this with their ability to bind tyrosine-phosphorylated c-ABL 1b [17].
• Grb2 binding is mediated through a phosphorylated tyrosine residue (Y177) located within a consensus Grb2 binding site encoded by the first exon of the BCR gene [32].

Regulatory relationships of BCR

• Sequences within the first exon of BCR are required to activate the transforming potential of BCR-ABL [1].
• Co-expression with BCR induces activation of the FES tyrosine kinase and phosphorylation of specific N-terminal BCR tyrosine residues [33].
• BACH2 was consistently upregulated (2-10-fold) in all 10 Ph+ lymphoid lines tested following BCR/ABL inhibition [34].
• In addition, the GM-CSF-induced-STAT5 activation was found to be weakened in all clones expressing BCR-ABL [35].
• Signal transducer and activator of transcription 5 (STAT5) is constitutively activated by BCR/ABL, the oncogenic tyrosine kinase responsible for chronic myelogenous leukemia [36].

Other interactions of BCR

• Inactivation of p53, which can accompany disease progression in human CML, impedes the response to imatinib in vitro and in vivo without preventing BCR-ABL kinase inhibition [15].
• Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2 [37].
• The study demonstrates that the BCR-FGFR1 fusion may occur in patients with apparently typical CML [38].
• The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA [39].
• We have examined expression of MCL-1 in primary CML cells and BCR/ABL-transformed cell lines [40].

Analytical, diagnostic and therapeutic context of BCR

• All four BCR loci segregate 100% concordantly with human chromosome 22 in a rodent-human somatic cell hybrid panel and are located at chromosome region 22q11.2 by chromosomal in situ hybridization [41].
• Based on our sequence analysis, we propose that initiation of translation occurs at nucleotide 471, such that the initial 927 amino acids of P210c-abl are derived from BCR sequences [21].
• Furthermore, with the use of immunogold labeling and electron microscopy, association of BCR with DNA, in particular heterochromatin, can be demonstrated even in quiescent cells [42].
• By using a reverse transcriptase-polymerase chain reaction assay, we show that both BCR alleles are expressed in the peripheral blood cells of normal individuals [43].
• Since other translocations in MPDs frequently involve tyrosine kinases, we designed a multiplex PCR to search for mRNA fusions between BCR and three potential partner genes at 4q12: KIT, KDR and PDGFRA [39].

References