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Gary  Reuther

Gary Reuther, PhD

Program: Molecular Oncology

Research Program: Cancer Biology & Evolution Program


  • Overview

    My lab focuses on understanding aberrant cytokine signaling pathways in myeloid neoplasms, with a particular focus on the JAK2 tyrosine kinase and identifying novel targets for therapeutic intervention.


    • Molecular Oncology
    • Malignant Hematology
    • Cancer Biology & Evolution Program
    • Molecular Oncology & Drug Discovery Program

    Education & Training


    • Duke University Medical Center, Durham, NC, PhD - Pharmacology


    • University of North Carolina, Chapel Hill, NC - Pharmacology
  • Research Interest

    My research is focused on characterizing aberrant cellular activities in hematological cancer to identify potential targets for much needed therapeutic strategies for patients. While past focus in the lab has been on acute myeloid leukemia, currently we are interested in understanding the significance of the activation of a protein called JAK2 in a family of blood diseases termed myeloproliferative neoplasms (MPNs). While patients with MPNs have an increased risk of potentially deadly coronary and blood clotting complications, MPNs also transform into acute myeloid leukemia, which is a steep clinical challenge. JAK2 is a tyrosine kinase that is deregulated by a variety of genetic mutations that are prevalent in MPNs and when expressed in mouse models induce an MPN-like phenotype. This further indicates JAK2 activity plays an important role in the development of MPNs in humans. However, JAK2 inhibitors have not had a significant effect at eliminating diseased cells from patients and thus do not readily or frequently induce remission. Therefore, there remains a need for alternative strategies to target MPN cells in patients. It is possible that combination treatments of JAK2 inhibitors with other small molecule targeted therapies or chemotherapies will provide benefit to MPN patients. Our research is focused on understanding JAK2 activation and signaling in MPNs and identifying possible alternative therapeutic targets in MPN cells. To this end, we utilize molecular biological, cell biological, biochemical, proteomic, and mouse model approaches to further our understanding of aberrant JAK2 signaling in MPNs and to develop improved JAK2 inhibitors and assess drug combination strategies that may lead to novel therapies to improve the lives of MPN patients.

  • Publications

    • Letson CT, Balasis ME, Newman H, Binder M, Vedder A, Kinose F, Ball M, Kruer T, Quintana A, Lasho TL, Finke CM, Almada LL, Grants JM, Zhang G, Fernandez-Zapico ME, Gaspar-Maia A, Lancet J, Komrokji R, Haura E, Sallman DA, Reuther GW, Karsan A, Rix U, Patnaik MM, Padron E. Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML. Clin Cancer Res. 2023 Aug.29(15):2919-2932. Pubmedid: 37223910. Pmcid: PMC10524644.
    • Pandey G, Kuykendall AT, Reuther GW. JAK2 inhibitor persistence in MPN: uncovering a central role of ERK activation. Blood Cancer J. 2022 Jan.12(1):13. Pubmedid: 35082276. Pmcid: PMC8792018.
    • Davis RR, Li B, Yun SY, Chan A, Nareddy P, Gunawan S, Ayaz M, Lawrence HR, Reuther GW, Lawrence NJ, Schönbrunn E. Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof. J Med Chem. 2021 Feb.64(4):2228-2241. Pubmedid: 33570945. Pmcid: PMC8327781.
    • Sharma V, Wright KL, Epling-Burnette PK, Reuther GW. Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms. Front Immunol. 2020 Nov.11:604142. Pubmedid: 33329600. Pmcid: PMC7734315.
    • Yue L, Sharma V, Horvat NP, Akuffo AA, Beatty MS, Murdun C, Colin C, Billington J, Goodheart WE, Sahakian E, Zhang L, Powers JJ, Amin NE, Lambert-Showers QT, Darville LN, Pinilla-Ibarz J, Reuther G, Wright K, Conti C, Lee JY, Zheng X, Ng PY, Martin MW, Marshall CG, Koomen JM, Levine RL, Verma A, Grimes HL, Sotomayor EM, Shao Z, Epling-Burnette PK. HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms. Blood. 2020 Jan.135(3):191-207. Pubmedid: 31750881. Pmcid: PMC6966930.
    • Fang B, Izumi V, Rix LLR, Welsh E, Pike I, Reuther GW, Haura EB, Rix U, Koomen JM. Lowering Sample Requirements to Study Tyrosine Kinase Signaling Using Phosphoproteomics with the TMT Calibrator Approach. Proteomics. 2020 Dec.20(24):e2000116. Pubmedid: 32865326. Pmcid: PMC7771371.
    • Kuykendall AT, Horvat NP, Pandey G, Komrokji R, Reuther GW. Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis. Cancers (Basel). 2020 Aug.12(8). Pubmedid: 32823910. Pmcid: PMC7464183.
    • Sarcar B, Gimbrone NT, Wright G, Remsing Rix LL, Gordian ER, Rix U, Chiappori AA, Reuther GW, Santiago-Cardona PG, Muñoz-Antonia T, Cress WD. Characterization of epidermal growth factor receptor (EGFR) P848L, an unusual EGFR variant present in lung cancer patients, in a murine Ba/F3 model. FEBS Open Bio. 2019 Oct.9(10):1689-1704. Pubmedid: 31314158. Pmcid: PMC6768113.
    • Mazzacurati L, Collins RJ, Pandey G, Lambert-Showers QT, Amin NE, Zhang L, Stubbs MC, Epling-Burnette PK, Koblish HK, Reuther GW. The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN. Blood Adv. 2019 Nov.3(22):3503-3514. Pubmedid: 31725895. Pmcid: PMC6880903.
    • Koblish H, Li YL, Shin N, Hall L, Wang Q, Wang K, Covington M, Marando C, Bowman K, Boer J, Burke K, Wynn R, Margulis A, Reuther GW, Lambert QT, Dostalik Roman V, Zhang K, Feng H, Xue CB, Diamond S, Hollis G, Yeleswaram S, Yao W, Huber R, Vaddi K, Scherle P. Preclinical characterization of INCB053914, a novel pan-PIM kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies. PLoS One. 2018 Jun.13(6):e0199108. Pubmedid: 29927999. Pmcid: PMC6013247.
    • Reuther GW. Myeloproliferative Neoplasms: Molecular Drivers and Therapeutics. Prog Mol Biol Transl Sci. 2017 Nov.144:437-484. Pubmedid: 27865464.
    • Ember SW, Lambert QT, Berndt N, Gunawan S, Ayaz M, Tauro M, Zhu JY, Cranfill PJ, Greninger P, Lynch CC, Benes CH, Lawrence HR, Reuther GW, Lawrence NJ, Schonbrunn E. Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics. Mol Cancer Ther. 2017 Jun.16(6):1054-1067. Pubmedid: 28336808. Pmcid: PMC5457702.
    • Gimbrone NT, Sarcar B, Gordian ER, Rivera JI, Lopez C, Yoder SJ, Teer JK, Welsh EA, Chiaporri AA, Schabath MB, Reuther GW, Dutil J, Garcia M, Ventosilla-Villanueva R, Vera-Valdivia L, Yabar-Berrocal A, Motta-Guerrero R, Santiago-Cardona PG, Muñoz-Antonia T, Cress WD. Somatic Mutations and Ancestry Markers in Hispanic Lung Cancer Patients. J Thorac Oncol. 2017 Dec.12(12):1851-1856. Pubmedid: 28911955. Pmcid: PMC5701827.
    • Basiorka AA, McGraw KL, De Ceuninck L, Griner LN, Zhang L, Clark JA, Caceres G, Sokol L, Komrokji RS, Reuther GW, Wei S, Tavernier J, List AF. Lenalidomide Stabilizes the Erythropoietin Receptor by Inhibiting the E3 Ubiquitin Ligase RNF41. Cancer Res. 2016 Jun.76(12):3531-3540. Pubmedid: 27197154. Pmcid: PMC4911265.
    • Mazzacurati L, Lambert QT, Pradhan A, Griner LN, Huszar D, Reuther GW. The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells. Oncotarget. 2015 Nov.6(37):40141-40157. Pubmedid: 26472029. Pmcid: PMC4741885.
    • Griner LN, McGraw KL, Johnson JO, List AF, Reuther GW. JAK2-V617F-mediated signalling is dependent on lipid rafts and statins inhibit JAK2-V617F-dependent cell growth. Brit J Haematol. 2013 Jan.160(2):177-187. Pubmedid: 23157224. Pmcid: PMC4505927.
    • Roll JD, Reuther GW. ALK-activating homologous mutations in LTK induce cellular transformation. PLoS One. 2012 Jul.7(2):e31733. Pubmedid: 22347506. Pmcid: PMC3276580.
    • Reuther GW. Recurring mutations in myeloproliferative neoplasms alter epigenetic regulation of gene expression. Am J Cancer Res. 2011 Nov.1(6):752-762. Pubmedid: 22016825. Pmcid: PMC3195930.
    • Lambert QT, Pradhan A, Roll JD, Reuther GW. Mutations in the transmembrane and juxtamembrane domains enhance IL27R transforming activity. Biochem J. 2011 Aug.438(1):155-164. Pubmedid: 21631431. Pmcid: PMC3145822.
    • Majumder A, Govindasamy L, Magis A, Kiss R, Polgár T, Baskin R, Allan RW, Agbandje-McKenna M, Reuther GW, Keseru GM, Bisht KS, Sayeski PP. Structure-function correlation of G6, a novel small molecule inhibitor of Jak2: indispensability of the stilbenoid core. J Biol Chem. 2010 Oct.285(41):31399-31407. Pubmedid: 20667821. Pmcid: PMC2951214.
    • Roll JD, Reuther GW. CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. Cancer Res. 2010 Oct.70(19):7347-7352. Pubmedid: 20807819. Pmcid: PMC2948596.
    • Griner LN, Reuther GW. Aggressive myeloid leukemia formation is directed by the Musashi 2/Numb pathway. Cancer Biol Ther. 2010 Nov.10(10):979-982. Pubmedid: 21084860.
    • Pradhan A, Lambert QT, Griner LN, Reuther GW. Activation of JAK2-V617F by components of heterodimeric cytokine receptors. J Biol Chem. 2010 May.285(22):16651-16663. Pubmedid: 20363735. Pmcid: PMC2878064.
    • Gordon GM, Lambert QT, Daniel KG, Reuther GW. Transforming JAK1 mutations exhibit differential signalling, FERM domain requirements and growth responses to interferon-γ. Biochem J. 2010 Dec.432(2):255-265. Pubmedid: 20868368. Pmcid: PMC4739517.
    • Rao R, Nalluri S, Fiskus W, Balusu R, Joshi A, Mudunuru U, Buckley KM, Robbins K, Ustun C, Reuther GW, Bhalla KN. Heat shock protein 90 inhibition depletes TrkA levels and signaling in human acute leukemia cells. Mol Cancer Ther. 2010 Aug.9(8):2232-2242. Pubmedid: 20663926. Pmcid: PMC3008427.
    • Gilkes DM, Pan Y, Coppola D, Yeatman T, Reuther GW, Chen J. Regulation of MDMX expression by mitogenic signaling. Mol Cell Biol. 2008 Mar.28(6):1999-2010. Pubmedid: 18172009. Pmcid: PMC2268405.
    • Reuther GW. JAK2 activation in myeloproliferative neoplasms: a potential role for heterodimeric receptors. Cell Cycle. 2008 Mar.7(6):714-719. Pubmedid: 18245948.
    • Cha JY, Lambert QT, Reuther GW, Der CJ. Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis. Mol Cancer Res. 2008 Mar.6(3):435-445. Pubmedid: 18337450.
    • Meyer J, Rhein M, Schiedlmeier B, Kustikova O, Rudolph C, Kamino K, Neumann T, Yang M, Wahlers A, Fehse B, Reuther GW, Schlegelberger B, Ganser A, Baum C, Li Z. Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, deltaTrkA. Leukemia. 2007 Oct.21(10):2171-2180. Pubmedid: 17673903.
    • Pradhan A, Lambert QT, Reuther GW. Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor. Proc Natl Acad Sci U S A. 2007 Nov.104(47):18502-18507. Pubmedid: 18003935. Pmcid: PMC2141806.
    • Ren Y, Chen Z, Chen L, Woods NT, Reuther GW, Cheng JQ, Wang HG, Wu J. Shp2E76K mutant confers cytokine-independent survival of TF-1 myeloid cells by up-regulating Bcl-XL. J Biol Chem. 2007 Dec.282(50):36463-36473. Pubmedid: 17942397. Pmcid: PMC3000740.
    • Lambert Q, Reuther G. Activation of Ras proteins by Ras guanine nucleotide releasing protein family members. Methods Enzymol. 2006.407:82-98. Pubmedid: 16757316.
    • Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG, Der CJ. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat Cell Biol. 2002 Aug.4(8):621-625. Pubmedid: 12134164.
    • Reuther G, Lambert Q, Rebhun J, Caligiuri M, Quilliam L, Der C. RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia. J Biol Chem. 2002 Aug.277(34):30508-30514. Pubmedid: 11880369.
    • Reuther G, Lambert Q, Booden M, Wennerberg K, Becknell B, Marcucci G, Sondek J, Caligiuri M, Der C. Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J Biol Chem. 2001 Jul.276(29):27145-27151. Pubmedid: 11373293.
    • Farwell D, Shera K, Koop J, Bonnet G, Matthews C, Reuther G, ColtreraMD, McDougall J, Klingelhutz A. Genetic and epigenetic changes in human epithelial cells immortalized by telomerase. Am J Pathol. 2000 May.156(5):1537-1547. Pubmedid: 10793065. Pmcid: PMC1876907.
    • Quackenbush R, Reuther G, Miller J, Courtney K, Pear W, Pendergast A. Analysis of the biologic properties of p230 Bcr-Abl reveals unique and overlapping properties with the oncogenic p185 and p210 Bcr-Abl tyrosine kinases. Blood. 2000 May.95(9):2913-2921. Pubmedid: 10779439.
    • Reuther G, Lambert Q, Caligiuri M, Der C. Identification and characterization of an activating TrkA deletion mutation in acute myeloid leukemia. Mol Cell Biol. 2000 Dec.20(23):8655-8666. Pubmedid: 11073967. Pmcid: PMC86471.
    • Reuther G, Buss J, Quilliam L, Clark G, Der C. Analysis of function and regulation of proteins that mediate signal transduction by use of lipid-modified plasma membrane-targeting sequences. Methods Enzymol. 2000 Dec.327:331-350. Pubmedid: 11044995.
    • Reuther G, Der C. The Ras branch of small GTPases: Ras family members don't fall far from the tree. Curr Opin Cell Biol. 2000 Apr.12(2):157-165. Pubmedid: 10712923.
    • Dai Z, Quackenbush R, Courtney K, Grove M, Cortez D, Reuther G, PendergastAM. Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway. Genes Dev. 1998 May.12(10):1415-1424. Pubmedid: 9585502 .
    • Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GW, Pendergast AM. Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway. Gene Dev. 1998 May.12(10):1415-1424. Pubmedid: 9585502. Pmcid: PMC316832.
    • Reuther J, Reuther G, Cortez D, Pendergast A, Baldwin AS J. A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes Dev. 1998 Apr.12(7):968-981. Pubmedid: 9531535 .
    • Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS. A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Gene Dev. 1998 Apr.12(7):968-981. Pubmedid: 9531535. Pmcid: PMC316671.
    • Cortez D, Reuther G, Pendergast A. The Bcr-Abl tyrosine kinase activates mitogenic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells. Oncogene. 1997 Nov.15(19):2333-2342. Pubmedid: 9393877 .
    • Reuther G, Pendergast A. The roles of 14-3-3 proteins in signal transduction. Vitam Horm. 1996 Dec.52:149-175. Pubmedid: 8909160 .
    • Reuther GW, Fu H, Cripe LD, Collier RJ, Pendergast AM. Association of the protein kinases c-Bcr and Bcr-Abl with proteins of the 14-3-3 family. Science. 1994 Oct.266(5182):129-133. Pubmedid: 7939633.
    • Reuther G, Fu H, Cripe L, Collier R, Pendergast A. Association of the protein kinases c-Bcr and Bcr-Abl with proteins of the 14-3-3 family. Science. 1994 Oct.266(5182):129-133. Pubmedid: 7939633 .
  • Grants

    • Title: Assessing novel therapeutics against RAS activation in models of myeloproliferative neoplasm and JAK2 inhibitor resistance
      Sponsor: Revolution Medicines Inc
      PI: Reuther, G.
    • Title: Targeting altered phosphatase-dependent signaling to overcome the inefficacy of targeted therapy in myeloproliferative neoplasms
      Sponsor: Nat Institutes of Health
      PI: Reuther, G.

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