The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains

Stanglmaier, Michael; Warmuth, Markus; Kleinlein, I; Reis, Samuel Roosevelt Campos dos; Hallek, Michael

doi:10.1038/sj.leu.2402778

Cited by 66 publications

(34 citation statements)

References 22 publications

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“…[77][78][79][80] Bcr-Abl directly interacts with multiple SFKs that subsequently switches the Abl kinase into an open, active conformation, perhaps permanently altering the enzymes cellular regulation and kinetics. 81 Phosphorylation of the SH2 and SH3 domains of Bcr-Abl by the SFKs may increase the activity of the Abl kinase, thus influencing its susceptibility to 82 Previous studies have demonstrated that in vitro treatment of imatinib-resistant cells with antisense RNA for Lyn partially restored imatinib susceptibility. 78 However, in imatinibresistant patients, there is limited clinical validation that inhibition of only one additional signaling cascade, such as the SFKs, is solely responsible for the clinical activity seen with dasatinib, a dual SFK and Abl kinase inhibitor.…”

Section: Drug Concentrationmentioning

confidence: 99%

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

2010

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Although only 5000 new cases of chronic myeloid leukemia (CML) were seen in the United States in 2009, this neoplasm continues to make scientific headlines year-after-year. Advances in understanding the molecular pathogenesis coupled with exciting developments in both drug design and development, targeting the initiating tyrosine kinase, have kept CML in the scientific limelight for more than a decade. Indeed, imatinib, a small-molecule inhibitor of the leukemia-initiating Bcr-Abl tyrosine kinase, has quickly become the therapeutic standard for newly diagnosed chronic phase-CML (CP-CML) patients. Yet, nearly one-third of patients will still have an inferior response to imatinib, either failing to respond to primary therapy or demonstrating progression after an initial response. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the cellular biology of drug trafficking, enzyme structure and function, and the rational design of novel small molecule enzyme inhibitors. Indeed, new classes of kinase inhibitors have recently been investigated in imatinibresistant CML. Understanding the pathogenesis of tyrosine kinase inhibitor resistance and the molecular rationale for the development of second and now third generation therapies for patients with CML will be keys to further disease control over the next 10 years.

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Section: Drug Concentrationmentioning

confidence: 99%

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

2010

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“…SRC kinases are involved in BCR-ABL-mediated transformation and have been implicated in imatinib resistance (Donato et al, 2003;Dai et al, 2004). Multiple domains of BCR-ABL interact with and activate SRC kinases independently of BCR-ABL kinase activity (Warmuth et al, 1997;Stanglmaier et al, 2003). The studies with dominant-negative mutants suggest that SRC kinases may contribute to the proliferation and survival of myeloid cell lines expressing BCR-ABL in vitro (Lionberger et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Identification and functional signature of genes regulated by structurally different ABL kinase inhibitors

et al. 2007

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Dasatinib is an ATP-competitive, multi-targeted SRC and ABL kinase inhibitor that can bind BCR-ABL in both the active and inactive conformations. From a clinical standpoint, dasatinib is particularly attractive because it has been shown to induce hematologic and cytogenetic responses in imatinib-resistant chronic myeloid leukemia patients. The fact because the combination of imatinib and dasatinib shows the additive/synergistic growth inhibition on wild-type p210 BCR-ABL-expressing cells, we reasoned that these ABL kinase inhibitors might induce the different molecular pathways. To address this question, we used DNA microarrays to identify genes whose transcription was altered by imatinib and dasatinib. K562 cells were cultured with imatinib or dasatinib for 16 h, and gene expression data were obtained from three independent microarray hybridizations. Almost all of the imatinib-and dasatinib-responsive genes appeared to be similarly increased or decreased in K562 cells; however, small subsets of genes were identified as selectively altered expression by either imatinib or dasatinib. The distinct genes that are selectively modulated by dasatinib are cyclin-dependent kinase 2 (CDK2) and CDK8, which had a maximal reduction of o5-fold in microarray screen. To assess the functional importance of dasatinib regulated genes, we used RNA interference to determine whether reduction of CDK2 and CDK8 affected the growth inhibition. K562 and TF-1BCR-ABL cells, pretreated with CDK2 or CDK8 small interfering RNA, showed additive growth inhibition with imatinib, but not with dasatinib. These findings demonstrate that the additive/ synergistic growth inhibition by imatinib and dasatinib may be mediated in part by CDK2 and CDK8.

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“…1 Bcr-Ablinduced Src kinase signaling is important in chronic myelogenous leukemia (CML). [2][3][4] Src kinases form a family of nine structurally homologous non-receptor intracellular tyrosine kinases that regulate signal transduction pathways involved in cell growth, differentiation and survival. 5 Src kinases are expressed in a tissue-specific manner and five of them, Hck, Lyn, Fgr, Lck and Blk, are strictly restricted to hematopoietic cells.…”

Section: Introductionmentioning

confidence: 99%

“…5 In myeloid cell lines, BcrAbl activates both Lyn and Hck kinases. 2,[6][7][8] In CML, overexpression and/or activation of Hck and Lyn are associated with disease progression. 4 It has been reported that bone marrow cells from mice lacking Hck, Lyn and Fgr, retrovirally transduced with BCR-ABL1, efficiently induced CML but not B-cell acute lymphocytic leukemia (ALL) in recipient mice.…”

Section: Introductionmentioning

confidence: 99%

Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia

et al. 2007

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Hck and Lyn are required in Philadelphia chromosome (Ph) positive acute lymphocytic leukemia (ALL). Here, we present evidence that the promoter CpG island of Hck, but not of Lyn, is aberrantly methylated in leukemia. Hck promoter DNA methylation was detected in 13 out of 23 (56.5%) hematopoietic and eight out of 10 (80%) non-hematopoietic cell lines, but not in normal controls. Treatment with 5-aza-2 0 -deoxycytidine induced demethylation and restoration of Hck mRNA and protein expression. Hck methylation (X15%) was detected in nine out of 44 (20%) patients with Ph negative ALL, and in one out 16 (6%) patients with Ph positive ALL, but not in patients with AML or chronic myelogenous leukemia. In this subset of patients, low levels of Hck methylation (10-15%) were observed in 26-30% of patients. Lyn methylation was observed in three out of 28 (10.7%) cell lines, but only in one out of 71 (1.4%) patients. Patients with Ph negative ALL and Hck methylation had a poorer prognosis. These data indicate that Hck may have tumor suppressor properties in BCR-ABL negative leukemia. Leukemia (2007) 21, 906-911.

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The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains

Cited by 66 publications

References 22 publications

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

Identification and functional signature of genes regulated by structurally different ABL kinase inhibitors

Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia

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