Human Oncology and Pathogenesis Program

Timothy A. Chan

James A. Fagin

Jason Huse

Marc Ladanyi

Ross L. Levine

Members of the Laboratory

Publications

Tashiro H., Isacson C., Levine R., Kurman R.J., Cho K.R., and Hedrick L. p53 Gene Mutations are Common in Uterine Serous Carcinoma and Occur Early in their Pathogenesis. American Journal of Pathology, 1997; 150:177-85.

Levine R.L., Cargile C.B., Blazes M.S., van Rees B., Kurman R.J., and Ellenson L.H. PTEN Mutations and Microsatellite Instability in Complex Atypical Hyperplasia, a Precursor Lesion to Uterine Endometrioid Carcinoma. Cancer Research, 1998;58:3254-58.

Esteller M., Levine R., Bailyn S.B., Ellenson L.H., and Herman J.G. hMLH1 Promoter Hypermethylation is Associated with the Microsatellite Instability Phenotype in Sporadic Endometrial Carcinomas. Oncogene, 1998;6:2413-2417.

Schlosshauer PW, Pirog EC, Levine R.L., and Ellenson L.H. Mutational Analysis of the CTNNB1 and APC Genes in Uterine Endometrioid Carcinoma. Modern Pathology, 2000;10:1066-1071.

Levine R.L., George D.J., and Kulke M.H. Incidental discovery of an appendiceal carcinoid tumor and a renal cell carcinoma. Clin Adv Hematol Oncol 1(2) 99-100.

Graux C., Cools J., Melotte C., Quentmeier H., Ferrando, A., Levine R., Vermeesch J.R., Stul M., Dutta B., Boeckx N., Bosly A., Heimann P., Uyttebroeck A., Somers R., MacLeod R.A.F., Drexler H.G., Look A.T., Gilliland D.G., Michaux L., Wlodarska I., Marynen P., and Hagemeijer. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nature Genetics, 2004;36:1084-1089.

Levine R.L.*, Wadleigh M.*, Sternberg D.W., Wlodarska I., Galinsky I., Stone R.M., DeAngelo D.J., Gilliland D.G., and Cools J. KIAA1509 is a novel PDGFRB fusion partner in imatinib-reponsive myeloproliferative disease associated with a t (5;14)(q33;q32). Leukemia, 2005;19:27-30. co-first authors

Levine R.L.*, Wadleigh M.*, Cools J., Ebert B.L., Wernig G., Huntly B.J.P., Boggon T.J., Wlodarska I., Clark J.J., Moore S., Adelsperger J., Koo S., Lee J.C., Gabriel S., Mercher T., D'Andrea A., Fröhling S., Dohner K., Marynen P., Vandenberghe P., Mesa R.A., Tefferi A., Griffin J.D., Eck M.J., Sellers W.R., Meyerson M., Golub T.R., Lee S.J., and Gilliland D.G. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocytosis, and myeloid metaplasia with myelofibrosis. Cancer Cell, 2005;7:387-397.
co-first authors

Steensma D.P., Dewald G.W., Lasho T.L., Powell H.L., McClure R.F., Levine R.L., Gilliland, D.G., and Tefferi A. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood, 2005;106:1207-1209.

Levine R.L., Loriaux M., Huntly B.J., Loh M., Beran M., Stoffregen E., Berger R., Clark J.J., Willis S.G,. Nguyen K., Flores N., Estey E., Gattermann N., Armstrong S., Look A.T., Griffin J.D., Bernard O.A., Gilliland D.G., Druker B.J., and Deininger M.W. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood, 2005;106:3377-3379.

Fröhling S., Lipka D.B., Kayser S., Scholl C., Schlenk R.F., Dohner H., Gilliland D.G., Levine R.L., and Dohner K. Rare occurrence of the JAK2V617F mutation in AML subtypes M5, M6, and M7. Blood, 2006;107:1242-1243.

Fröhling S., Scholl C., Gilliland D.G., and Levine R.L. Genetics of myeloid malignancies; pathogenetic and clinical implications. Journal of Clinical Oncology, 2005;23:6285-6295.

Cario H., Goerttler P.S., Steimle C., Levine R.L., and Pahl H.L. The JAK2V617F mutation is acquired secondary to the predisposing alteration in familial polycythaemia vera. Br J Haematol. 2005;130(5):800-801.

Lu X.*, Levine R.*, Tong W., Wernig G., Pikman Y., Zarnegar S., Gilliland D.G., and Lodish H. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proceedings of the National Academy of Sciences. 2005;102:18962-18967.
co-first authors

Levine R.L., Belisle C., Wadleigh M., Lee S., Chagnon P., Gilliland D.G., and Busque L. X-Inactivation based Clonality Analysis and Quantitative JAK2V617F Assessment Reveals a Strong Association between Clonality and JAK2V617F in PV but not ET/MMM, and Identifies a Subset of JAK2V617F Negative ET and MMM Patients with Clonal Hematopoiesis. Blood, 2006;107:4139-4141

Wernig G., Mercher T., Okabe R., Levine R.L., Lee B.H., and Gilliland D.G. Expression of JAK2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood, 2006;107(11):4274-81.

Mercher T. Wernig G., Moore S.A., Levine R.L., Gu T.L., Fröhling S., Cullen D., Polakiewicz R.D., Bernard O.A., Boggon T.J., Lee B.H., and Gilliland D.G. JAK2T875N is a novel activating mutation associated with an acute megakaryoblastic leukemia phenotype. Blood, 2006;108(8):2770-9.

Pikman Y., Lee, B.H., Mercher T., McDowell E., Ebert B.L., Gozo M., Cuker A., Wernig G., Moore S., Galinsky I., DeAngelo D.J., Clark J.J., Lee S.J., Golub T.R., Wadleigh M., Gilliland D.G., and Levine R.L. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. Public Library of Science Medicine 2006:3(7):e27.

Pardanani A., Levine R.L., Lasho T.L., Pikman Y., Mesa R.A., Wadleigh M., Steensma D.P., Elliott M.A., Wolanskyj A.P., Hogan W.J., McClure R.F., Litzow M.R., Gilliland D.G., and Tefferi A. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 Patients. Blood, 2006 Nov 15;108(10):3472-6.

Lasho T.L., Pardanani A., McClure R.F., Mesa R.A., Levine, R.L., Gilliland D.G., and Tefferi A. Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in clonal load over time. British Journal of Haematology, 2006 Dec;135(5):683-7.

Duan Z., Bradner J., Greenberg E., Levine R., Foster R., Mahoney J., and Seiden M.V. The small molecule SD-1029, inhibits Stat3 nuclear translocation and increases chemotherapy sensitivity in human cancer cells. Clinical Cancer Research, 2006 Nov 15;12(22):6844-52.

Levine R.L. and Wernig G. Role of JAK-STAT Signaling in the Pathogenesis of Myeloproliferative Disorders. Hematology American Society of Hematology Education Program, 2006;:233-9

Lee J.C., Vivanco I., Beroukhim R., Huang J.H., Feng W.L., Debiasi R.M., Yoshimoto K., King J.C., Nghiemphu P., Yuza Y., Xu Q., Greulich H., Thomas R.K., Paez J.G., Peck T.C., Linhart D.J., Glatt K.A., Getz G., Onofrio R., Ziaugra L., Levine R.L., Gabriel S., Kawaguchi T., O'neill K., Khan H, Liau LM, Nelson SF, Rao PN, Mischel P, Pieper RO, Cloughesy T, Leahy DJ, Sellers WR., Sawyers C.L., Meyerson M., Mellinghoff I.K. Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain. Public Library of Science Medicine, 2006 Dec 19;3(12):e485.

Levine R.L. and Gilliland D.G. JAK-2 mutations and their relevance to myeloproliferative disease. Current Opinion in Hematology, 2007 Jan;14(1):43-7.

Scott, L.M., Tong, W., Levine, R.L., Scott, M.A.., Beer, P.A., Stratton, M.R., Futreal, P.A., Erber, W.N., McMullin, M.F, Harrison, C.N., Warren, A.J., Gilliland, D.G., Lodish, H.F., and Green, A.R. Mutations of JAK2 exon 12 reveal a distinct variant of polcythemia vera. New England Journal of Medicine, 2007 Feb 1;356(5):459-68.

Mesa R.A., Verstovsek S., Cervantes F., Barosi G., Reilly J.T., Dupriez B., Levine R., Le Bousse-Kerdiles M.C., Wadleigh M., Campbell P.J., Silver R.T., Vannucchi A.M., Deeg H.J., Gisslinger H., Thomas D., Odenike O., Solberg L.A., Gotlib J., Hexner E., Nimer S.D., Kantarjian H., Orazi A., Vardiman J.W., Thiele J., Tefferi A. On behalf of the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leukemia Research, 2007 Jun;31(6):737-40.

Pardanani A., Hood J., Lasho T., Levine R.L. , Martin M.B., Noronha G., Finke C., Mak C.C., Mesa R., Zhu H., Soll R., Gilliland D.G., Tefferi A. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia. 2007 Aug;21(8):1658-68.

Yamamoto G., Nannya Y., Kato M., Sanada M., Levine R.L., Kawamata N., Hangaishi A., Kurokawa M., Chiba S., Gilliland D.G., Koeffler H.P., Ogawa S. Highly sensitive method for genomewide detection of allelic composition in nonpaired, primary tumor specimens by use of affymetrix single-nucleotide-polymorphism genotyping microarrays. American Journal of Human Genetics 2007 Jul;81(1):114-26. Epub 2007 Jun 5.

Levine R.L., Pardanani A., Tefferi A., Gilliland D.G. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nature Reviews Cancer. 2007 Sep;7(9):673-83.

Lee B.H., Tothova Z., Levine R.L., Anderson K. Byza-Vidas N., Cullen D.E., M cDowell E.P., Adelsperger J., Frohling S., Huntly B.J., Beran M., Jaconsen S.E., Gilliland D.G. FLT3 Mutations Confer Enhanced Proliferation and Survival Properties to Multipotent Progenitors in a Murine Model of Chronic Myelomonocytic Leukemia. Cancer Cell 2007 Oct 12(4): 367-80.

Pikman Y. and Levine, R.L. Advances in the molecular characterization of Philadelphia-negative chronic myeloproliferative disorders. Curr Opin Oncol. 2007 Nov;19(6):628-634.

Fröhling S., Scholl C., Levine R.L., Loriaux M., Boggon T.J., Bernard O.A., Berger R., Döhner H., Döhner K., Ebert B.L., Teckie S., Golub T.R., Jiang J., Schittenhelm M.M., Lee B.H., Griffin J.D., Stone R.M., Heinrich M.C., Deininger M.W., Druker B.J., and Gilliland D.G. Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles. Cancer Cell. 2007 Dec;12(6):501-13.

Levine R.L. JAK2V617F: you can't have too much. Blood. 2008 Apr 15;111(8):3913.

Wernig G., Kharas M.G., Okabe R., Moore S.A., Leeman D.S., Cullen D., Gozo M., McDowell E.P., Levine R.L., Doukas J., Mak C.C., Noronha G., Martin M., Ko Y.D., Lee B.H., Soll R., Tefferi A., Hood J.D., Gilliland D.G.G. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008 Apr;13(4):311-2.

Loriaux M.M.*, Levine R.L. *, Tyner J.W., Fröhling S., Scholl C., Stoffregen E.P., Wernig G., Erickson H., Eide C.A., Berger R., Bernard O.A., Griffin J.D., Stone R.M., Lee B.H., Meyerson M., Heinrich M.C., Deininger M.W., Gilliland D.G., and Druker B.J. High throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood. 2008 May 1;111(9):4788-96. co-first authors

Lipka D.B., Hoffmann L.S., Heidel F., Markova B., Blum M.C., Breitenbuecher F., Kasper S., Kindler T., Levine R.L., Huber C., Fischer T. LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells. Mol Cancer Ther. 2008 May;7(5):1176-84.

Jamal R, Bélisle C, Lessard MC, Hébert J, Roy DC, Levine R, Busque L. Evidence suggesting the presence of a stem cell clone anteceding the acquisition of the JAK2-V617F mutation. Leukemia. 2008 Jul;22(7):1472-4.

Marks J.L., Gong Y., Chitale D., Golas B., McLellan M.D., Kasai Y., Ding L., Mardis E.R., Wilson R.K., Solit D., Levine R., Michel K., Thomas R.K., Rusch V.W., Ladanyi M., Pao W. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Research, 2008 Jul 15;68(14):5524-8.

Koppikar P, and Levine R.L. JAK2 and MPL mutations in myeloproliferative neoplasms. Acta Haematol. 2008;119(4):218-25.

Levine R.L. and Gilliland D.G. Myeloproliferative Disorders. Blood, 2008 Sep 15;112(6):2190-8.

Kilpivaara, O and Levine R.L. JAK2 and MPL Mutations in Myeloproliferative Neoplasms - Discovery and Science. Leukemia, 2008 Oct;22(10):1813-7.

Kawamata N., Ogawa S., Yamamoto G., Lehmann S., Levine R.L., Pikman Y., Nannya Y., Sanada M., Miller C.W., Gilliland D.G., Koeffler H.P. Genetic profiling of myeloproliferative disorders by single-nucleotide polymorphism oligonucleotide microarray. Experimental Hematology, 2008 Nov;36(11):1477-85.

Brown J.R., Levine R.L., Thompson C., Basile G., Gilliland D.G., Freedman A.S. Systematic genomic screen for tyrosine kinase mutations in CLL. Leukemia, 2008 Oct;22(10):1966-9.

Levine R.L. and Heaney M. New advances in the pathogenesis and therapy of essential thrombocythemia Hematology. American Society of Hematology Education Program, 2008;76-82.

Abdel-Wahab O.I. and Levine R.L. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2008 Oct 23. [Epub ahead of print]

Bernard L., Belisle C., Mollica L., Provost S., Roy D.C., Gilliland D.G., Levine R.L., Busque L. Telomere length is severely and similarly reduced in JAK2V617F-positive and -negative myeloproliferative neoplasms. Leukemia 2009 Feb;23(2):287-91.

Tyner J.W., Erickson H., Deininger M.W., Willis S.G., Eide C.A., Levine R.L., Heinrich M.C., Gattermann N., Gilliland D.G., Druker B.J., Loriaux M.M. High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients. Blood. 2009 Feb 19;113(8):1749-55.

Busque L., Paquette Y., Provost S., Roy D.C., Levine R.L., Mollica L., and Gilliland D.G. Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood. 2009 Feb 6.

Tefferi A., Pardanani A., Lim K-H., Abdel-Wahab O., Lasho T.L., Patel J., Gangat N., Finke C.M., Schwager S., Mullally A., Li C-Y., Hanson C.A., Mesa R., Bernard O., Delhommeau F., Vainchenker W., Gilliland D.G., and Levine R.L. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis, Leukemia published online March 8, 2009.

Tefferi A., Lim K-H., Abdel-Wahab O., Lasho T.L., Patel J., Hanson C.A., Pardanani A., Gilliland D.G., and Levine R.L. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML, Leukemia published online March 8, 2009.

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.* and Levine R.L.* A germline JAK2 SNP is associated with predisposition to the development of JAK2 V617F-positive myeloproliferative neoplasms. Nature Genetics published online March 15, 2009.
co-corresponding authors

Mercher, T., Raffel, G.D, Moore, S.A., Cornejo, M.G., Baudry-Bluteau, D., Cagnard, N., Jesneck, J.L., Pikman, Y., Cullen, D., Williams, I.R., Akashi, K., Shigematsu, H., Bourquin, J.P., Giovannini, M., Vainchenker, W., Levine, R.L., Lee, B.H., Bernard, O.A., and Gilliland, D.G. The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. Journal of Clinical Investigation published online March 17, 2009.

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