Ross L. Levine: Publications

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Ross L. Levine: Publications

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  1. Shih A., Jiang Y., Maydan C., Shank K., Pandey S., Barreyo L., Antony-Debre I., Viale A., Socci N., Sun Y., Robertson A., Cavatore M., Stanchina E., Hricik T., Rapaport F., Woods B., Wei C., Hatlen M., Baljevic M., Nimer S.D., Tallman M., Paietta E., Cimmino L., Aifantis I., Steidl U., Mason C., Melnick A.*, Levine R.L.* Mutational Cooperativity Linked to Combinatorial Epigenetic Gain of Function in Acute Myeloid Leukemia. Cancer Cell, 2015 Apr 13;27(4):502-15, PMCID: PMC4518555
  2. Kleppe M., Koche R., Zou L., van Galen P., De Groote S., Dong L.1, Papalexi E., Hill C., Keller M., Somasundara A.V.H., Cordner K., Reyes J., Roberts J., Witkins M., Rapaport F., Teruya-Feldstein J., Jun Qi3, Rampal R., Bernstein B.E., Bradner J.E., Levine R.L., Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell in press, PMCID pending.
  3. Viny A.D., Ott C.J., Spitzer B., Rivas M., Meydan C., Papalexi E., Yelin D., Shank K., Reyes J., Chiu A., Romin Y., Boyko V., Thota S., Maciejewski J.P., Melnick A., Bradner J.E., Levine R.L. Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. Journal of Experimental Medicine. 2015 Oct 19; 212(11):1819-32. PMCID: PMC4612085
  4. Guryanova O.A., Shank K., Spitzer B., Luciani L., Koche R., Garrett-Bakelman F.E., Chezi Ganzel, Durham B., Mohanty A., Hoermann G., Pronier E., Rivera S.A., Chramiec A.G., Lennart Bastian, Keller M.D., Tovbin D., Loizou E., Weinstein A.R., Rodriguez Gonzalez A.A., Lieu Y., Rowe J.M., Pastore F., McKenney A.S., Krivtsov A.V., Sperr W.R., Cross J., Tallman M.S., Arcila M.E., Abdel-Wahab O., Armstrong S.A., Kubicek S., Staber P.B., Gönen M., Paietta E.M., Melnick A.M., Nimer S.D., Mukherjee S.*, Levine R.L.* DNMT3A R882 mutations promote anthracycline resistance in acute myeloid leukemia through impaired nucleosome remodeling. Nature Medicine, 2016 Dec;22(12):1488-1495. PMCID: PMC5359771

Molecular Pathogenesis of MPNs: Our laboratory has had a longstanding interest in the molecular pathogenesis of MPNs, dating back to when I was a postdoctoral fellow. In recent years we have identified a common inherited predisposition allele in the JAK2 locus that enhances the risk of somatic mutations and have performed somatic mutational and gene expression studies that have illustrated the role that mutations in the JAK-STAT pathway and in epigenetic regulators play in MPN pathogenesis.
 

  1. Kilpivaara O., Mukherjee S., Schram A.M., Wadleigh M., Mullally A., Ebert B.L., Bass A., Marubayashi S., Heguy A., Garcia-Manero G., Kantarjian H., Offit K., Stone R.M., Gilliland D.G., Klein R.J., *Levine R.L.* A germline JAK2 SNP is associated with predisposition to the development of JAK2 V617F-positive myeloproliferative neoplasms. Nature Genetics, 2009 Apr;41(4):455-9, *co-corr. Authors
  2. Rampal R, Al-Shahrour F, Abdel-Wahab O, Patel JP, Brunel JP, Mermel CH, Bass AJ, Pretz J, Ahn J, Hricik T, Kilpivaara O, Wadleigh M, Busque L, Gilliland DG, Golub TR, Ebert BL, Levine R.L. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood. 2014 May 29;123(22). PMCID: PMC4041169
  3.  Rampal R., Ahn J., Abdel-Wahab O., Nahas M., Wang K., Lipson D., Otto G., Yelensky R., Hricik T., McKenney A., Chung Y.R., Pandey S., van den Brink M, Armstrong S., Dogan A., Intlekofer A., Manshouri T., Park C. Vertovsek S., Rapaport F., Stephens P., Miller V., Levine R.L. Genomic and Functional Analysis of Leukemic Transformation of Myeloproliferative Neoplasms. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5401-10

Development of Targeted Therapies for MPN Patients: We have investigated and credentialed targeted therapies for MPN patients in murine models and primary patient samples. This includes JAK inhibitors, which are now approved, and HSP90 inhibitors, which are in trials at MSK based on our work and which are showing significant clinical efficacy. We have also investigated mechanisms of resistance to JAK inhibitors.
 

  1. Koppikar P.✝, Bhagwat N.✝ Kilpivaara O.✝, Manshouri T., Adli M., Hricik T Liu F., Saunders L.M., Mullally A., Abdel-Wahab O., Leung L., Weinstein A., Marubayashi S., Goel A., Gönen M., Estrov Z., Ebert B.L., Chiosis G., Nimer S.D., Bernstein B.E., Verstovsek S., Levine R.L. Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy. Nature, 2012 Sep 6;489(7414):155-9.✝co-first
  2. Bhagwat N., Koppikar P., Keller M., Marubyashi S., Shank K., Rampal R., Qi J., Kleppe M., Patel H.J., Shah S.K., Taldone T., Bradner J.E., Chiosis G., Levine R.L. Improved Targeting of JAK2 Leads to Increased Therapeutic Efficacy in Myeloproliferative Neoplasms. Blood, 2014 Mar 27;123(13):2075-83 PMCID: PMC3968390
  3. Kleppe M., Kwak M., Koppikar P., Riester M., Keller M., Bastian L., Hricik T., Bhagwat N., McKenney A.S., Papalexi E., Abdel-Wahab O., Rampal R., Marubayashi S., Chen J.J., Romanet V., Fridman J.S., Bromberg J., Teruya-Feldstein J., Murakami M., Radimerski T., Michor F., Fan R.*, Levine R.L.* JAK-STAT Pathway Activation in Malignant and Non-Malignant Cells Contributes to MPN Pathogenesis and Therapeutic Response. Cancer Discovery. 2015 Mar;5(3):316-31. [PMID 25572172]
  4. Meyer S.C., Keller MD, Chiu S., KoppikarP., GuryanovaO.A., RapaportF., XuK., ManovaK., PankovD., O’Reilly R.J., Kleppe M., McKenney A.S., Shih A.H., Shank K., Ahn J., PapalexiE., SpitzerB., SocciN., VialeA., Mandon E., Ebel N., Andraos R., Rubert J., Dammassa E., RomanetV., Dölemeyer A., Zender M., Heinlein M., RampalR., Weinberg R.S., Hoffman R. , SellersW.R., Hofmann F., Murakami M., Baffert F., Gaul C., RadimerskiT.*, Levine R.L.* CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.  Cancer Cell, 2015 Jul 13;28(1):15-28, PMID in process.

Role that Mutations in Epigenetic Modifiers Play in Leukemic Transformation: We have investigated the role of novel mutations in epigenetic modifiers, including in TET2, ASXL1, and IDH1/2, using epigenomic studies in patient samples and model systems as well as mechanistic studies. These have allowed us to delineate novel mechanisms of transformation by these mutations in epigenetic modifiers.
 

  1. Busque L., Patel J.P., Figueroa, M.E., Vasanthakumar A., Provost S., Hamilou Z., Mollica L., Li J., Viale, A., Heguy, A., Hassimi M., Socci N., Bhatt P.K., Gönen, M., Mason C.E., Melnick, A., Godley L.A., Brennan C., Abdel-Wahab, O., Levine, R.L. Recurrent Somatic TET2 Mutations in Normal Elderly Individuals With Clonal Hematopoiesis. Nature Genetics, 2012 Nov; 44(11):1179-81. PMC3483435
  2. Abdel-Wahab O.A., Adli M., LaFave L.M., Gao J., Hricik T., Shih A.H., Pandey S., Patel J., Chung Y.R., Koche R., Perna F., Zhao X., Taylor J.E., Park C.Y., Carroll M., Melnick A., Nimer S.D., Jaffe J.D., Aifantis I., Bernstein B.E. *, Levine R.L.* ASXL1 Mutations Promote Myeloid Transformation Through Loss of PRC2-Mediated Gene Repression. Cancer Cell, 2012 Aug 14;22(2):180-93. ✝co-first authors *co-corresponding authors
  3.  Shih A., Jiang Y., Maydan C., Shank K., Pandey S., Barreyo L., Antony-Debre I., Viale A., Socci N., Sun Y., Robertson A., Cavatore M., Stanchina E., Hricik T., Rapaport F., Woods B., Wei C., Hatlen M., Baljevic M., Nimer S.D., Tallman M., Paietta E., Cimmino L., Aifantis I., Steidl U., Mason C., Melnick A.*, Levine R.L.* Mutational Cooperativity Linked to Combinatorial Epigenetic Gain of Function in Acute Myeloid Leukemia. Cancer Cell, 2015 Apr 13;27(4):502-15, PMID in process.
  4.  LaFave L.M., Béguelin W., Koche R., Teater M., Spitzer B., Chramiec A., Papalexi E., Keller M., Hricik T., Konstantinoff K., Micol J.B., Durham B., Knutson S.K., Campbell J.E., Blum G., Shi X., Doud E., Krivtsov A., Chung Y.R., Khodos I., DeStanchina E., Ouerfelli O., Adusumilli P., Thomas P.M., Kelleher N.L., Luo M., Keilhack H., Abdel-Wahab O., Melnick A., Armstrong S.A., Levine R.L. Bap1 loss leads to EZH2-dependent transformation. Nature Medicine. 2015 Nov;21(11):1344-9. PMC4636469.

Genetic Studies in AML: We have performed high-throughput mutational profiling of AML patients, including in large, homogeneously treated phase III clinical trial cohorts. We have showed that mutational profiling can be used to develop a novel, robust prognostic schema, which is now being translated to the clinical setting at MSK and nationally.
 

  1. Patel J.P. Gönen, M. Figueroa, M.E., Fernandez, H., Sun, Z., Racevskis, J., Van Vlierberghe, P., Dolgalev, I., Thomas, S., Aminova, O., Huberman, K., Cheng, J., Viale, A., Socci, N., Heguy, A., Cherry, A., Vance, G., Higgins, R.R., Ketterling, R., Gallagher, R.E., Litzow, M., van den Brink, M.R.M., Lazarus, H.M., Rowe, J., Luger S., Ferrando, A., Paietta, E., Tallman, M.S., Melnick, A., Abdel-Wahab, O., Levine, R.L. Prognostic and Therapeutic Relevance of Integrated Genetic Profiling in AML. New England Journal of Medicine. 2012, Mar 22;366(12):1079-89. NIHMS366015

Development of Animal Models of Myeloid Malignancies: We have used conditional murine knockout and knock-in approaches to develop novel murine models in which mutations in epigenetic modifiers are engineered in hematopoietic cells to develop genetically accurate models of MPNs, myelodysplastic syndromes, and AML.
 

  1. Moran-Crusio K.=, Reavie L.=, Shih A. =, Abdel-Wahab O.A. Ndiaye-Lobry D., Lobry C., Figueroa M., Vasanthakumar A. Patel J., Zhao X., Perna F., Pandey S., Madzo J., Song C., Dai Q., He C., Ibrahim S., Beran M., Zavadil J., Nimer S.D., Melnick A., Godley L.,, Aifantis I.*, Levine R.L.*Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation.  Cancer Cell, 12 July 2011, 20:1-14. NIHMS312230 =co-first authors *co-corresponding authors
  2. Abdel-WahabO., Gao J., Adli M.A., Dey A., TrimarchiT., Chung Y.R., Kuscu C., Hricik T., Ndiaye-LobryD., LLa Fave L.M., Koche R., Shih A.H.,GuryanovaO.A., Kim E., Li S., Pandey S., Shin J.Y., TelisL., Liu J., Bhatt P.K., Monette S., ZhaoX., Mason C.E., Park C.Y., Bernstein B.E., AifantisI.*, Levine R.L.*.  Deletion of Asxl1 Results in Myelodysplasia and Severe Developmental Defects in Vivo. Journal of Experimental Medicine, 2013 Nov 18;210(12):2641-59. *co-corresponding authors
  3. Viny A.D., Ott C.J., Spitzer B., Rivas M., Meydan C., Papalexi E., Yelin D., Shank K., Reyes J., Chiu A., Romin Y., Boyko V., Thota S., Maciejewski J.P., Melnick A., Bradner J.E., Levine R.L. Dose-dependent role of the cohesion complex in normal and malignant hematopoiesis. Journal of Experimental Medicine. 2015 Oct 19; 212(11):1819-32. PMCID: PMC4612085