Disease relevance of Bcr

• Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia [1].
• Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia [2].
• It is well accepted that the Bcr-Abl oncoprotein encoded by the Philadelphia chromosome is responsible for causing chronic myelogenous leukemia (CML) [3].
• The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML [4].
• Bap-1 interacts with full-length c-Bcr and with the chimeric Bcr-Abl tyrosine kinase of Philadelphia chromosome (Ph1)-positive human leukemias [5].

High impact information on Bcr

• The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl [4].
• These results connect Bcr in vivo with the regulation of Rac-mediated superoxide production by the NADPH-oxidase system of leukocytes and suggest a link between Bcr function and the cell type affected in Ph-positive leukemia [6].
• Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound [7].
• Association of the protein kinases c-Bcr and Bcr-Abl with proteins of the 14-3-3 family [5].
• The sequence of the 3BP-1 protein is similar to that of a COOH-terminal segment of Bcr and to guanosine triphosphatase-activating protein (GAP)-rho, which suggests that it might have GAP activity for Ras-related proteins [8].

Chemical compound and disease context of Bcr

• We determined the effects of AMN107 and/or LBH589 in Bcr-Abl-expressing human K562 and LAMA-84 cells, as well as in primary chronic myelogenous leukemia (CML) cells [9].
• Bcr-Abl constitutes a deregulated tyrosine kinase involved in the pathogenesis of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL) [10].
• Our data indicate that PD180970 is active against several Bcr-Abl mutations that are resistant to imatinib and support the notion that developing additional Abl kinase inhibitors would be useful as a treatment strategy for chronic myelogenous leukemia [11].
• AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia [12].
• Herein, we show that STI571, an inhibitor of Bcr-Abl in chronic myelogenous leukemia, blocks activation of c-Abl in the response of mouse embryo fibroblasts and human U-937 myeloid leukemia cells to hydrogen peroxide (H(2)O(2)) [13].

Biological context of Bcr

• The ability of Bcr-Abl to protect cytokine-dependent 32D myeloid cells from death induced by cytokine deprivation or DNA damage does not, however, require functional NF-kappaB [14].
• Treatment with LBH589 also depleted Bcr-Abl levels and induced apoptosis of IM-resistant primary human CML cells, including those with expression of Bcr-AblT315I [9].
• We investigated the role of poly(ADP-ribose) polymerase (PARP) activity in imatinib-induced cell death in Bcr-Abl-positive cells [15].
• These combined data demonstrate a prominent role for Abr and Bcr in the regulation of glial cell morphology and reactivity, and consequently in granule cell migration during postnatal cerebellar development in mammals [16].
• In the current study this hypothesis was tested in vivo by introducing a Bcr/Abl P190 transgene into mice lacking endogenous bcr protein [17].

Anatomical context of Bcr

• Mouse bone marrow cells transduced with retroviral vectors encoding either of two oncogenic Bcr-Abl isoforms (p210(Bcr-Abl) and p185(Bcr-Abl)) induce B cell lympholeukemias when transplanted into lethally irradiated mice [2].
• Abnormal function of astroglia lacking Abr and Bcr RacGAPs [16].
• In addition, the Bcr/1-242-Abl mutant has a reduced capacity to induce focus formation in fibroblasts [18].
• Neoplastic spleens from these mice usually contained b3a2 Bcr-Abl transcripts [3].
• NS-187 also inhibited leukemic cells harboring wild-type Bcr-Abl growth in the central nervous system, which sometimes becomes a sanctuary for leukemic cells under imatinib treatment [19].

Associations of Bcr with chemical compounds

• Importantly, this activation is dependent on the tyrosine kinase activity of Bcr-Abl and partially requires Ras [14].
• Although cells expressing the Bcr-Abl kinase can proliferate in the absence of IL-7, they remain responsive to this cytokine, which can reduce their sensitivity to imatinib [2].
• AMN107 (Novartis Pharmaceuticals, Basel, Switzerland) has potent in vitro and in vivo activity against the unmutated and most common mutant forms of Bcr-Abl [9].
• This binding occurs in a phosphotyrosine-dependent manner at Bcr sites of Bcr-Abl [18].
• Bcr/Abl expression stimulates integrin function in hematopoietic cell lines [20].

Physical interactions of Bcr

• In concordance with this, the Abl ATP-binding pocket domain of Bcr/Abl in the resistant cells did not contain point mutations which would make the protein Imatinib resistant [21].

Enzymatic interactions of Bcr

• Western blot analysis of -/- and +/+ lymphomas showed that the related Crk protein was tyrosine phosphorylated and could be found complexed with Bcr-Abl P190 [22].
• Cbl is one of the major tyrosine-phosphorylated proteins in Bcr-Abl-expressing cells [23].

Regulatory relationships of Bcr

• We found that imatinib kills Bcr/Abl(+) leukemic cells by triggering the Bcl-2-regulated apoptotic pathway [24].
• Osteopontin was identified by microarray analysis as highly upregulated in cells expressing elevated amounts of Bcr-Abl [25].

Other interactions of Bcr

• This study implicates NF-kappaB as an important component of Bcr-Abl signaling [14].
• IKK activity is not deregulated by Bcr-Abl and v-Abl [10].
• Development of NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor [19].
• Here we demonstrate that the simultaneous disruption of two negative regulators of Rac, Abr and Bcr, in mice leads to specific abnormalities in postnatal cerebellar development [16].
• Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic [24].

Analytical, diagnostic and therapeutic context of Bcr

• In the present study, RNA in situ hybridization was used to explore the normal cellular function of Bcr in rodent brain and hematopoietic organs [26].
• Dasatinib has been shown to inhibit growth of Bcr-Abl-dependent chronic myeloid leukemia xenografts in nude mice [27].
• Experimental animal models, such as transgenic mice, have demonstrated unambiguously that Bcr/Abl is capable of inducing leukemogenesis [28].
• Most importantly, in a transplantation model of CML, Bcr-Abl was capable of inducing fatal leukemia in mice in the absence of c-Cbl protein [29].
• Immunoprecipitation experiments revealed that CK2alpha is associated with normal c-Abl in mouse NIH3T3 fibroblasts and with the Bcr-Abl fusion protein in K562 human myeloid leukemia cells [30].

References