This is a competitive renewal of our NCI funded grant to study the contributions of trisomy 21 to hematologic malignancies. Children with Down syndrome (DS), who have trisomy 21 in their cells, are remarkably predisposed to leukemia, with an estimated 1 in 10 newborns exhibiting transient myeloproliferative disorder (TMD) and 1 in 500 DS children developing acute megakaryocytic leukemia (AMKL) by the age of five. In addition to myeloid leukemia, children with DS have a 20-fold increased risk of B-cell acute lymphoblastic leukemia (B-ALL). We hypothesize that that trisomy 21 directly and functionally contributes to the malignant transformation of hematopoietic cells. In particular, we believe that increased expression of the kinase DYRK1A and chromosome assembly factor CHAF1B directly contribute to the increased incidence of leukemia in this population. With a greater knowledge of these genes on human chromosome 21 (Hsa21) and the specific events that occur in the evolution of these diseases, improved diagnostics and therapies can be discovered. During the previous funding period, we made many important discoveries regarding the role of trisomy 21 and GATA1 mutations in these diseases. We: 1) Identified several candidate megakaryocytic leukemia promoting genes in the Down syndrome critical region of chromosome 21, including DYRK1A, CHAF1B and ERG; 2) Showed that the Ts1Rhr animal model of DS, which is trisomic for 31 genes that parallel the human Down syndrome critical region, faithfully mimics DS-AMKL when GATA1 and MPL mutations, two alterations that are associated with DS-AMKL, are introduced; 3) Demonstrated that overexpression of ERG and the presence of the leukemic GATA1 isoform GATA1s cooperate with AKT in aberrant megakaryopoiesis; 4) Revealed that Dyrk1a is essential for both B and T cell development through its regulation of cyclin D3 stability and that inhibition of Dyrk1a leads to a lymphoid, but not myeloid, deficiency, 5) Discovered that evolution of trisomy 21 to transient leukemia and then AMKL is associated with progressive epigenetic changes; and 6) Showed, in collaboration with David Weinstock, that trisomy of HMGN1 promotes B-ALL. In this renewal, we will focus on two candidate leukemia promoting genes on chromosome 21, the kinase DYRK1A and the nucleosome assembly factor CHAF1B.
Our specific aims are to: 1) Determine the role of DYRK1A and its substrate STAT3 in leukemia in children with DS, and 2) Define the contributions of CHAF1B to normal and malignant hematopoiesis. In addition to providing insights into the role of trisomy 21 in DS leukemia, this research is also relevant to general B-cell ALL and other leukemias with acquired trisomy 21, such as hyperdiploid ALL.
Children with Down syndrome, who have three copies of chromosome 21, face a 500-fold increased risk of developing acute megakaryoblastic leukemia and a 20-fold increased risk of pre-B cell acute lymphoblastic leukemia. Our research will uncover the mechanisms by which three copies of two genes on chromosome 21, the kinase DYRK1A and the chromatin assembly factor CHAF1B, contribute to normal and malignant hematopoiesis. Our work will also aid in the development of new, targeted therapies for these leukemias.
|Volk, Andrew; Liang, Kaiwei; Suraneni, Praveen et al. (2018) A CHAF1B-Dependent Molecular Switch in Hematopoiesis and Leukemia Pathogenesis. Cancer Cell 34:707-723.e7|
|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|
|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|
|Crispino, John D; Horwitz, Marshall S (2017) GATA factor mutations in hematologic disease. Blood 129:2103-2110|
|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|
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