Oncogenic signaling: new insights and controversies from chronic myeloid leukemia

Etten, Richard A. Van

doi:10.1083/jcb1767oia14

Cited by 14 publications

(17 citation statements)

References 15 publications

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“…In the case of chronic myelogenous leukemia (CML), an apical lesion has been identified, namely, the BCR-ABL oncoprotein, a constitutively active tyrosine kinase that activates multiple other antiapoptotic pathways including NF-kB, AKT, and STAT5, among others (1). The discovery and identification of this mutant oncoprotein sparked the development of multiple BCR-ABL kinase inhibitors (e.g., imatinib mesylate, dasatinib, nilotinib), which have shown impressive activity in this disease.…”

Section: Pathway Addictionmentioning

confidence: 99%

Cotargeting survival signaling pathways in cancer

2008

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Section: Pathway Addictionmentioning

confidence: 99%

Cotargeting survival signaling pathways in cancer

2008

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“…However two challenging problems persist: the progression of the disease to blast crisis and resistance to kinase inhibition. 1 Continued investigation of BCR-ABL1 kinase signaling will provide insight into these problems. Members of the Src kinase family, which regulate proliferation, differentiation, and motility, 2 are known downstream targets of BCR-ABL1.…”

Section: Introductionmentioning

confidence: 99%

BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia

Ban¹,

Gao²,

Amin³

et al. 2008

Blood

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Chronic myelogenous leukemia (CML) in IntroductionThe management of chronic myelogenous leukemia (CML) has been revolutionized by kinase inhibitors that were developed in response to cues from biologic studies of the BCR-ABL1 oncogene. However two challenging problems persist: the progression of the disease to blast crisis and resistance to kinase inhibition. 1 Continued investigation of BCR-ABL1 kinase signaling will provide insight into these problems. Members of the Src kinase family, which regulate proliferation, differentiation, and motility, 2 are known downstream targets of BCR-ABL1. In myeloid cell lines, BCR-ABL1 activates Lyn and Hck. 3,4 Several reports link growth, survival, and imatinib resistance of Philadelphia chromosome-positive (Ph ϩ ) leukemias to Lyn kinase expression and activation. 5,6 However, reports examining Fyn, a ubiquitously expressed Src family member, are sparse. Of note, phase-specific gene expression in CML using microarray analyses revealed that Fyn gene expression was linked to imatinib relapse. 7 In addition, a separate study using combined systems biology and gene expression approaches in Ph ϩ acute lymphoblastic leukemia (ALL) specimens identified Fyn as a hub for signaling. 8 Here we show that Fyn protein expression is increased in patients with blast-crisis CML compared with chronic-phase disease. By examining effects of silencing Fyn using shRNA, we find that Fyn transduces a mitogenic signal. Collectively, our results identify a novel effect of BCR-ABL1-up-regulation of Fyn-and delineate consequences of the observed up-regulation. MethodsPatient specimens were used for this study and were collected after informed consent was obtained in accordance with the Declaration of Antibodies, chemicals, and cell linesAntibodies were purchased from sources outlined in Document S1 (available on the Blood website; see the Supplemental Materials link at the top of the online article). Imatinib was kindly provided by Dr Elisabeth Buchdunger at Novartis Pharmaceuticals (Basel, Switzerland). Murine growth factor-dependent pro-B lymphoid BaF3 cell lines transformed with vector, wild-type BCR-ABL1, or imatinib-resistant mutant BCR-ABL1 were kindly provided by Dr Charles Sawyers 9 and were cultured as previously described. 9 K562 cells, TonB210 cells stably expressing a tetracyclineinducible BCR-ABL1 expression vector (kindly provided by Dr George Daley, Children's Hospital Boston, Harvard Medical School, MA), 10 and mouse 32D and 32Dp210 cells were maintained in RPMI1640 medium with 10% FBS supplemented. Mouse 32D cells were supplemented with 10% WEHI-cultured conditioned medium as a source of interleukin-3 (IL-3) in addition to 10% FBS. Design of shRNA to FynK562 cells were transfected with Fyn shRNA and control vectors (TranSilent human shRNA from Panomics, Redwood, CA) using the Nucleofector system kit V and transfection program T-16 (Amaxa Biosystems, Cologne, Germany). Lentiviral knockdown of Fyn and rescue design is detailed in Document S1. To generate the rescue construct, 4 nucleo...

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“…The generation of the BCR/ABL kinase, ATP-competitive inhibitor imatinib mesylate (IM) has revolutionized the therapy of CML, since this drug is highly effective in the CP of the disease (11). However, there are 3 major problems with IM-based therapy: (a) the limited response of CML-BC or Ph 1 B cell acute lymphoblastic leukemia (ALL) patients to IM (11)(12)(13); (b) the development of resistance caused in approximately 40% of cases by mutations in the BCR/ABL kinase domain, which impair the ability of IM to interact with the protein (14)(15)(16)(17)(18); and (c) the relative insensitivity of Ph 1 CML stem cells to IM (19).…”

Section: Introductionmentioning

confidence: 99%

Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells

Bellodi

Lidonnici²,

Hamilton³

et al. 2009

J. Clin. Invest.

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529

447

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Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210 BCR/ABL -expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca 2+ , suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.

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Oncogenic signaling: new insights and controversies from chronic myeloid leukemia

Cited by 14 publications

References 15 publications

Cotargeting survival signaling pathways in cancer

Cotargeting survival signaling pathways in cancer

BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia

Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells

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