The majority of infant acute megakaryocytic leukemias (AMKL) in non-Down Syndrome children have a unique chromosomal translocation, t(1;22). This translocation fuses two novel genes believed to be transcription factors, OTT (a.k.a. RBM15) and MAL (a.k.a. MKL1/MRTF-A/BSAC), and results in the expression of a chimeric protein. Homologous structural motifs within the fusion have been identified in proteins known to be involved in differentiation, proliferation and leukemogenesis. To elucidate the pathophysiology induced by the OTT-MAL fusion protein, mice have been generated using a knock-in approach to express OTT-MAL from the OTT locus. By expressing the fusion protein from the endogenous OTT promoter, the stoichiometry and expression pattern of OTT-MAL found in the human leukemia should be reproduced. Evolving data suggests subtle differences in gene dosage and regulation have a critical impact on leukemogenesis and normal megakaryopoiesis. ? ? Identification of the pathways by which OTT-MAL may induce leukemogenesis will require a more comprehensive understanding of the component genes, OTT and MAL as their hematopoietic roles are unknown. Deletion of OTT or MAL in mice will provide an invaluable reagent in defining the pathways dysregulated by OTT-MAL in terms of gene expression and physiology. The role of OTT-MAL in t(1;22) AMKL will be investigated using routine models to address the following questions: ? ? Specific Aim 1. What are the consequences of OTT-MAL expression in mice? ? ? Specific Aim 2. What is the in vivo physiologic role of OTT and which pathways of endogenous OTT are utilized by the OTT-MAL fusion protein? ? ? Specific Aim 3. What role does MAL function have in normal physiology and in OTT-MAL-mediated dysregulation? ? ? The establishment and analysis of a murine model of t(1;22) AMKL will provide new opportunities for the study of pathogenesis in AMKL, potential therapeutic interventions and fundamental insight into megakaryocyte development. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA111399-03
Application #
7176783
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$134,379
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Raffel, Glen D; Chu, Gerald C; Jesneck, Jonathan L et al. (2009) Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen. Mol Cell Biol 29:333-41
Mercher, Thomas; Raffel, Glen D; Moore, Sandra A et al. (2009) The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. J Clin Invest 119:852-64
Raffel, Glen D; Mercher, Thomas; Shigematsu, Hirokazu et al. (2007) Ott1(Rbm15) has pleiotropic roles in hematopoietic development. Proc Natl Acad Sci U S A 104:6001-6