Effects of the JAK2 Inhibitor, AZ960, on Pim/BAD/BCL-xL Survival Signaling in the Human JAK2 V617F Cell Line SET-2

Gozgit, Joseph M.; Bebernitz, Geraldine; Patil, Pankaj; Ye, Minwei; Parmentier, Julie; Wu, Joy T.; Su, Nancy; Wang, Tao; Ioannidis, Stephanos; Davies, Audrey M.; Huszar, Dennis; Zinda, Michael

doi:10.1074/jbc.m803813200

Cited by 90 publications

(100 citation statements)

References 44 publications

(81 reference statements)

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“…Interestingly, pSTAT1 has been observed in a subpopulation of cells in extramedullary hematopoietic tissue from a JAK2 V617F -positive PV patient, and the activation of STAT1 has recently been shown to promote an ET versus a PV phenotype, which indicates the potential of STAT1 as an additional modifying factor of MPN disease progression. 41,42 These findings further highlight an interconnection between STAT1 and JAK2 V617F -STAT3/5 signal transduction, and support the concept that these proteins should be examined in concert to guide the use of JAK2 inhibitors like BMS-911543 in MPN and other malignancies. AVP, TMM, HW, DY, BP, XH, RV, YZ, SUR, GLT, LL, MMG, PRM, HS, JH, SLE, YB, EF, TLT KWM, EM, CM, FYL, AW and MVL are employees of Bristol-Myers Squibb, which generated BMS-911543 for clinical trials.…”

Section: Discussionmentioning

confidence: 59%

“…A unifying feature of this transcriptional profile was a core set of regulated genes involved in cytokine-receptor signaling including CISH, PIM1 and SOCS2, previously shown to be regulated by JAK2 pathway inhibition. 29,41 In addition to these changes, we also unexpectedly found STAT1 protein and transcript levels as well as its phosphorylation to be downregulated by JAK2 inhibition. Importantly, the regulation of STAT1 and the associated gene products was correlated highly with JAK2 on-target pharmacology and was shared across multiple inhibitors.…”

Section: Discussionmentioning

confidence: 84%

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Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

et al. 2011

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We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2 V617F -positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2 V617F -expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 84%

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

et al. 2011

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“…Consequently, caspase 3/7 activation and an associated increase in PARP and Mcl-1 cleavage occurred upon cotreatment with ruxolitinib and navatoclax. Aspects of these results have been noted in other disorders (13,20,21,36). Gozgit et al reported that inhibition of JAK2 blocked production of the Pim1/2 kinases and resulted in a corresponding decrease in BAD phosphorylation (13), and Will et al demonstrated that apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells (20).…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence indicate that activation of the JAK/ STAT pathway up-regulates the expression of antiapoptotic Bcl-2 family proteins and that inhibition of this pathway induces expression of proapoptotic BH3-only proteins, thereby inducing apoptosis (13,20,21). Treatment with ruxolitinib or IL-2 withdrawal reduced expression of p-STAT5 in all IL-2-dependent ATL cell lines (SI Appendix, Fig.…”

Section: Matrix Screening Highlights Ruxolitinib Drug Combinations Thatmentioning

confidence: 99%

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Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Zhang

Griner

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokinedependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.adult T-cell leukemia | Janus kinase | ruxolitinib | navitoclax T -cell leukemia/lymphoma represents ∼10% of lymphoid malignancies. Genetic alterations affecting members of the Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) were discovered in a variety of T-cell malignancies (1, 2). Furthermore, increases in the common γc cytokine concentrations that signal through the JAK1/3, STAT3/5 pathway have been demonstrated in angioimmunoblastic T-cell lymphoma, gamma delta T-cell lymphoma, and adult T-cell leukemia (ATL), thereby identifying effective therapeutic targets.ATL is an aggressive T-cell malignancy characterized by the clonal expansion of CD4 + CD25 + T lymphocytes that develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1 (HTLV-1) (3-5). Clinically, ATL is subclassified into four subtypes: smoldering, chronic, lymphomatous, and acute (4, 5). Presently, there is no curative therapy for ATL (4, 5). In search of effective therapies, we examined key signaling pathways that confer a proliferation and viability advantage to ATL cells. It was noted that the HTLV-1-encoded Tax (transactivator from the X-gene region) is associated with increased Bcl-xL (B-cell lymphoma-extra large) expression in ATL cells (6). Furthermore, we reported two autocrine loops (IL-2/IL-2Rα, IL-15/IL-15Rα) and one paracrine loop that in...

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Nuclear JAK2: Form and Function in Cancer

Qian

Yao

2011

The Anatomical Record

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The conventional view of Janus kinase 2 (JAK2) is a nonreceptor tyrosine kinase which transmits information to the nucleus via the signal transducer and activator of transcriptions (STATs) without leaving the cytoplasm. However, accumulating data suggest that JAK2 may signal by exporting from cytoplasm to nucleus, where it guides the transcriptional machinery independent of STATs protein. Recent studies demonstrated that JAK2 is a crucial component of signaling pathways operating in the nucleus. Especially the latest landmark discovery confirmed that JAK2 goes into the nucleus and directly interacts with nucleoproteins, such as histone H3 at tyrosine 41 (H3Y41), nuclear factor 1-C2 (NF1-C2) and SWI/SNF-related helicases/ATPases (RUSH)-1a, indicating that JAK2 has a fresh nuclear function. Nuclear JAK2 is linked to a variety of cellular functions, such as cell cycle progression, apoptosis and genetic instability. The balance between these functions is an essential factor in determining whether a cell remains benign or becomes malignant. The aim of this review is intended to summarize the state of our knowledge on nuclear localization of JAK2 and nuclear JAK2 pathways, and to highlight the emerging roles for nuclear JAK2 in carcinogenesis.

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Effects of the JAK2 Inhibitor, AZ960, on Pim/BAD/BCL-xL Survival Signaling in the Human JAK2 V617F Cell Line SET-2

Cited by 90 publications

References 44 publications

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Nuclear JAK2: Form and Function in Cancer

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