DF/HCC Program Affiliation

Co-Leader, Leukemia Program
Member, Cancer Genetics Program

DF/HCC Associations

Member, Center Scientific Council

Research Abstract

Our laboratory studies the molecular genetic basis of human leukemias, myeloproliferative syndromes and myeloproliferative disorders. We have cloned genes causally implicated in the pathogenesis of these disorders by using positional cloning strategies. For example, we have cloned a number of acquired chromosomal translocation breakpoints associated with leukemia and myelodysplastic syndrome. Cloning of these breakpoints has identified fusion genes such as TEL/PDGFßR, TEL/AML1, MOZ-TIF2, HIP1/PDGFßR, and TEL/ABL, that are responsible for transformation of hematopoietic cells. Another strategy has been to clone disease genes in pedigrees with inherited leukemia syndromes using generalized linkage analysis. This approach has recently led to the identification of loss of function mutations in the AML1 gene as the cause of a familial leukemia syndrome called the FPD/AML syndrome. We are now in the process of characterizing the biochemical and transforming properties of these fusion proteins in cell culture systems, and well as in murine models of leukemia. These studies should provide insight into the molecular pathogenesis of leukemia, and should shed light on normal mechanisms of control of hematopoietic development. In addition, these data may allow for design of better approaches to therapy of hematologic malignancies in humans

Publications

• Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman JW. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007 May 8;
  PMID: 17488875
• Raffel GD, Mercher T, Shigematsu H, Williams IR, Cullen DE, Akashi K, Bernard OA, Gilliland DG. Ott1(Rbm15) has pleiotropic roles in hematopoietic development. Proc Natl Acad Sci U S A 2007 Apr 3; 104(14):6001-6
  PMID: 17376872
• Gu TL, Mercher T, Tyner JW, Goss VL, Walters DK, Cornejo MG, Reeves C, Popova L, Lee K, Heinrich MC, Rush J, Daibata M, Miyoshi I, Gilliland DG, Druker BJ, Polakiewicz RD. A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia. Blood 2007 Apr 13;
  PMID: 17360941
• Tefferi A, Gilliland DG. Oncogenes in myeloproliferative disorders. Cell Cycle 2007 Mar; 6(5):550-66
  PMID: 17351342
• Scholl C, Bansal D, Döhner K, Eiwen K, Huntly BJ, Lee BH, Rücker FG, Schlenk RF, Bullinger L, Döhner H, Gilliland DG, Fröhling S. The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis. J Clin Invest 2007 Apr; 117(4):1037-48
  PMID: 17347684
• Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, Gilliland DG, Zhang Y, Kaelin WG. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 2007 Mar 9; 128(5):889-900
  PMID: 17320163
• Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007 Feb 1; 356(5):459-68
  PMID: 17267906
• Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 2007 Jan 26; 128(2):309-23
  PMID: 17254969
• Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegué E, DePinho RA, Gilliland DG. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007 Jan 26; 128(2):325-39
  PMID: 17254970
• Ihle JN, Gilliland DG. Jak2: normal function and role in hematopoietic disorders. Curr Opin Genet Dev 2007 Feb; 17(1):8-14
  PMID: 17208428
• Levine RL, Gilliland DG. JAK-2 mutations and their relevance to myeloproliferative disease. Curr Opin Hematol 2007 Jan; 14(1):43-7
  PMID: 17133099
• Lasho TL, Pardanani A, McClure RF, Mesa RA, Levine RL, Gilliland DG, Tefferi A. Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in mutant allele burden over time. British Journal of Haematology 2006 Dec; 135(5):683-7
  PMID: 17107350
• Bansal D, Scholl C, Fröhling S, McDowell E, Lee BH, Döhner K, Ernst P, Davidson AJ, Daley GQ, Zon LI, Gilliland DG, Huntly BJ. Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model. Proc Natl Acad Sci U S A 2006 Nov 7; 103(45):16924-9
  PMID: 17068127
• Tomasson MH, Sternberg DW, Williams IR, Carroll M, Cain D, Aster JC, Ilaria RL, Van Etten RA, Gilliland DG. Fatal myeloproliferation, induced in mice by TEL/PDGFbetaR expression, depends on PDGFbetaR tyrosines 579/581. J Clin Invest 2000 Feb; 105(4):423-32
  PMID: 10683371
• Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999 Oct; 23(2):166-75
  PMID: 10508512
• Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria R, Marynen P, Gilliland DG. Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. EMBO J 1998 Sep 15; 17(18):5321-33
  PMID: 9736611