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ABSTRACT: The discovery of activating mutations in JAK2 and MPL in a majority of patients with myeloproliferative neoplasms (MPN) has led to the rapid clinical development of several JAK kinase inhibitors. Of these, the JAK1/2 inhibitor, ruxolitinib (INCB018424, Incyte Corporation) was recently approved for the treatment of patients with myelofibrosis (MF). JAK inhibitors have effectively reduced splenomegaly and high cytokine levels in patients leading to improvements in quality of life. However, they have not been successful in eliminating the mutant clone in a majority of patients. In vitro studies using saturation mutagenesis screens have revealed several mutations in JAK2 that confer resistance to JAK inhibitors. Nevertheless, these mutations have not been identified so far in JAK inhibitor-treated patients. A recent study from our laboratory demonstrated that chronic JAK kinase inhibition leads to JAK inhibitor persistence via transphosphorylation of JAK2 through other JAK kinase family members. This phenomenon is seen in cell lines, mouse models and patient samples. The JAK inhibitor persistent cells, however, still remain JAK2 dependent and therefore combination therapies that target JAK2 and other components of the JAK-STAT pathway along with JAK inhibitors may provide additional benefits and improve clinical outcomes in these patients.
International journal of hematology 05/2013; · 1.17 Impact Factor
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Emmanuel L Gautier,
Marit Westerterp, Neha Bhagwat,
Serge Cremers,
Alan Shih,
Omar Abdel-Wahab,
Dieter Lütjohann,
Gwendalyn J Randolph,
Ross L Levine,
Alan R Tall,
Laurent Yvan-Charvet
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ABSTRACT: A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models of myeloproliferative disorders, including mice with defective cholesterol efflux pathways and two models based on expression of human leukemia disease alleles, we uncovered a mechanism by which proliferating and inflammatory myeloid cells take up and oxidize glucose during the feeding period, contributing to energy dissipation and subsequent loss of adipose mass. In vivo, lentiviral inhibition of Glut1 by shRNA prevented myeloproliferation and adipose tissue loss in mice with defective cholesterol efflux pathway in leukocytes. Thus, Glut1 was necessary to sustain proliferation and potentially divert glucose from fat storage. We also showed that overexpression of the human ApoA-I transgene to raise high-density lipoprotein (HDL) levels decreased Glut1 expression, dampened myeloproliferation, and prevented fat loss. These experiments suggest that inhibition of Glut-1 and HDL cholesterol-raising therapies could provide novel therapeutic approaches to treat the energy imbalance observed in myeloproliferative disorders.
Journal of Experimental Medicine 01/2013; · 13.85 Impact Factor
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Priya Koppikar, Neha Bhagwat,
Outi Kilpivaara,
Taghi Manshouri,
Mazhar Adli,
Todd Hricik,
Fan Liu,
Lindsay M Saunders,
Ann Mullally,
Omar Abdel-Wahab, [......],
Sachie Marubayashi,
Aviva Goel,
Mithat Gönen,
Zeev Estrov,
Benjamin L Ebert,
Gabriela Chiosis,
Stephen D Nimer,
Bradley E Bernstein,
Srdan Verstovsek,
Ross L Levine
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ABSTRACT: The identification of somatic activating mutations in JAK2 (refs 1–4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.
Nature 07/2012; 489(7414):155-9. · 36.28 Impact Factor
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Maria E Figueroa,
Omar Abdel-Wahab,
Chao Lu,
Patrick S Ward,
Jay Patel,
Alan Shih,
Yushan Li, Neha Bhagwat,
Aparna Vasanthakumar,
Hugo F Fernandez, [......],
Valeria R Fantin,
Elisabeth Paietta,
Bob Löwenberg,
Jonathan D Licht,
Lucy A Godley,
Ruud Delwel,
Peter J M Valk,
Craig B Thompson,
Ross L Levine,
Ari Melnick
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ABSTRACT: Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect.
Cancer cell 12/2010; 18(6):553-67. · 25.29 Impact Factor
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Sachie Marubayashi,
Priya Koppikar,
Tony Taldone,
Omar Abdel-Wahab,
Nathan West, Neha Bhagwat,
Eloisi Caldas-Lopes,
Kenneth N Ross,
Mithat Gönen,
Alex Gozman,
James H Ahn,
Anna Rodina,
Ouathek Ouerfelli,
Guangbin Yang,
Cyrus Hedvat,
James E Bradner,
Gabriela Chiosis,
Ross L Levine
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ABSTRACT: JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following the discovery of activating JAK2 mutations in the majority of patients with MPN. However, to date JAK2 inhibitor treatment has shown limited efficacy and apparent toxicities in clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated efficacy in cell line and mouse models of the MPN polycythemia vera (PV) and essential thrombocytosis (ET) by disrupting JAK2 protein stability. JAK2 physically associated with both HSP90 and PU-H71 and was degraded by PU-H71 treatment in vitro and in vivo, demonstrating that JAK2 is an HSP90 chaperone client. PU-H71 treatment caused potent, dose-dependent inhibition of cell growth and signaling in JAK2 mutant cell lines and in primary MPN patient samples. PU-H71 treatment of mice resulted in JAK2 degradation, inhibition of JAK-STAT signaling, normalization of peripheral blood counts, and improved survival in MPN models at doses that did not degrade JAK2 in normal tissues or cause substantial toxicity. Importantly, PU-H71 treatment also reduced the mutant allele burden in mice. These data establish what we believe to be a novel therapeutic rationale for HSP90 inhibition in the treatment of JAK2-dependent MPN.
The Journal of clinical investigation 10/2010; 120(10):3578-93. · 15.39 Impact Factor
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ABSTRACT: Recurrent somatic mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes that result in the accumulation of D-2-hydroxyglutarate (D-2-HG) have been identified in malignant gliomas and in acute myeloid leukemia (AML). However, the function of this metabolite in normal and malignant tissues remains uncertain. A report in the current issue of Science describes a germline IDH2 mutation in a subset of patients with a rare metabolic disorder--D-2-hydroxyglutaric aciduria-that is similar to mutations seen in cancer patients. These observations further elucidate the effects of IDH mutations on normal and malignant cells.
Science translational medicine 10/2010; 2(54):54ps50. · 7.80 Impact Factor
