Children with Down syndrome face a 10-20 fold increased risk of developing some form of leukemia and a 500-fold increased risk of acute megakaryoblastic leukemia (DS-AMKL). Furthermore, infants with DS are commonly and uniquely affected by a related myeloid disease, named transient myeloproliferative disorder (TMD). We recently demonstrated that the hematopoietic transcription factor GATA1 is mutated in nearly all cases of both TMD and DS-AMKL. In every case, the mutation results in loss of expression of full-length GATA-1, but allows for translation of a shortened isoform, GATA-1s, which retains both DMA binding zinc fingers, but is missing the N-terminal transactivation domain. We have found that GATA-1s can rescue the terminal differentiation of GATA-1 deficient megakaryocytes, but it fails to restrict their hyperproliferative phenotype: these observations lead us to hypothesize that an imbalance of gene regulation due to the expression of this short isoform contributes to the pathogenesis of TMD and DS-AMKL. With respect to the role of trisomy 21 in AMKL, we discovered that the most widely used mouse model of DS, Ts65Dn mice, develop a myeloproliferative disorder (MPD) characterized by thrombocytosis, myelofibrosis and a marked expansion in the megakaryocyte lineage. This suggests that trisomy 21 directly contributes to aberrant megakaryopoiesis and provides us with a platform for identifying the specific genes involved. Here we propose to define the role of GATA1 mutations and trisomy 21 in AMKL. Specifically we plan to: 1) characterize the myeloproliferative disease in mouse models of DS, 2) identify the mouse orthologs of human chromosome 21 genes that contribute to this disease (and, by extension, to DS-AMKL), and 3) assess the genetic interaction between GATA1, trisomy 21 and mutant forms of JAK kinases in AMKL, using mouse models. The results of our research will increase our understanding of how GATA1 mutations contribute to the initiation or progression of leukemia in DS and may also lead the identification of novel leukemia disease genes on human chromosome 21. In addition, since much leukemia, such as hyper- diploid ALL, acquire additional copies of chromosome 21 during their evolution;our work will likely have relevance to other more common forms of hematopoietic malignancies. Lay Summary: This research will provide insight to the cause of leukemia in children with Down syndrome and may lead to improved therapies and diagnostics. Furthermore, the research may also have impact on the etiology of other human blood diseases, such as myeloproliferative disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101774-08
Application #
7822842
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
2003-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2010
Total Cost
$301,396
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Hu, Deqing; Gao, Xin; Cao, Kaixiang et al. (2017) Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification. Mol Cell 65:460-475.e6
Crispino, John D; Horwitz, Marshall S (2017) GATA factor mutations in hematologic disease. Blood 129:2103-2110
Liang, Kaiwei; Volk, Andrew G; Haug, Jeffrey S et al. (2017) Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia. Cell 168:59-72.e13
Fisher, Joseph B; McNulty, Maureen; Burke, Michael J et al. (2017) Cohesin Mutations in Myeloid Malignancies. Trends Cancer 3:282-293
Lee, P; Bhansali, R; Izraeli, S et al. (2016) The biology, pathogenesis and clinical aspects of acute lymphoblastic leukemia in children with Down syndrome. Leukemia 30:1816-23
Thompson, Benjamin J; Bhansali, Rahul; Diebold, Lauren et al. (2015) DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3. J Exp Med 212:953-70
Goldenson, B; Crispino, J D (2015) The aurora kinases in cell cycle and leukemia. Oncogene 34:537-45
Volk, Andrew; Crispino, John D (2015) The role of the chromatin assembly complex (CAF-1) and its p60 subunit (CHAF1b) in homeostasis and disease. Biochim Biophys Acta 1849:979-86
Sakamoto, Kathleen M; Grant, Steven; Saleiro, Diana et al. (2015) Targeting novel signaling pathways for resistant acute myeloid leukemia. Mol Genet Metab 114:397-402
Malinge, Sébastien; Chlon, Tim; Doré, Louis C et al. (2013) Development of acute megakaryoblastic leukemia in Down syndrome is associated with sequential epigenetic changes. Blood 122:e33-43

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