Acute leukemias that bear chromosomal translocations at 11q23 possess rearrangements of the Mixed Lineage Leukemia gene (MLL, HRX, ALL-1). More than 40 different MLL translocations have been reported, but the t(9;11) (MLL-AF9) and the t(4;11) (MLL-AF4) are particularly common. MLL-AF9 is most frequently identified in leukemias diagnosed as AML whereas MLL-AF4 is found solely in leukemias diagnosed as ALL or mixed-lineage leukemia. Patients with MLL-AF4 rearranged leukemias have a poor prognosis. This is particularly true for infant leukemia where approximately 80% of cases will harbor rearrangement of the MLL gene. We have previously demonstrated that human lymphoblastic leukemias harboring MLL-rearrangements possess a unique gene expression profile that suggests they arise from an early hematopoietic progenitor. This approach also identified the receptor tyrosine kinase FLT3 as a potential therapeutic target in this disease. Using a murine model system of MLL-AF9 induced AML, we have recently identified a hematopoietic stem cell (HSC) associated gene expression program activated in granulocyte macrophage progenitors (GMP) during their conversion to leukemia stem cells (LSC). In these studies we noted repression of cebp/a as a component of the MLL-AF9 induced program.
In specific aim 1 we will asses specific genes found highly expressed in LSC, and perform a high-throughput screen to identify small molecules that reverse the LSC program.
In specific aim 2 of this proposal we will work with members of project 3 to interrogate the role of cebp/a in MLL-rearranged leukemia.
In specific aim 3 we will work with members of projects 1 and 2 to develop a conditional murine model of MLL-AF4 induced leukemia and assess the potential for cooperation with mutant FLT3 alleles during leukemogenesis. Such a model will not only allow identification of progenitor populations susceptible to MLL-AF4 induced transformation, but also provide a much-needed model for assessment of therapeutics developed in projects 1 and 2.
|Numata, Akihiko; Kwok, Hui Si; Kawasaki, Akira et al. (2018) The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. Nat Commun 9:1622|
|Brown, Fiona C; Still, Eric; Koche, Richard P et al. (2018) MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia. Cancer Discov 8:478-497|
|Manley, Paul W; Weisberg, Ellen; Sattler, Martin et al. (2018) Midostaurin, a Natural Product-Derived Kinase Inhibitor Recently Approved for the Treatment of Hematological MalignanciesPublished as part of the Biochemistry series ""Biochemistry to Bedside"". Biochemistry 57:477-478|
|Ebert, Benjamin L; Libby, Peter (2018) Clonal Hematopoiesis Confers Predisposition to Both Cardiovascular Disease and Cancer: A Newly Recognized Link Between Two Major Killers. Ann Intern Med 169:116-117|
|DiNardo, Courtney D; Pratz, Keith W; Letai, Anthony et al. (2018) Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19:216-228|
|Brien, Gerard L; Remillard, David; Shi, Junwei et al. (2018) Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. Elife 7:|
|Weinberg, Olga K; Gibson, Christopher J; Blonquist, Traci M et al. (2018) Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities. Haematologica 103:626-633|
|Hoshii, Takayuki; Cifani, Paolo; Feng, Zhaohui et al. (2018) A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. Cell 172:1007-1021.e17|
|Gutierrez-Martinez, Paula; Hogdal, Leah; Nagai, Manavi et al. (2018) Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat Cell Biol 20:413-421|
|Gooptu, Mahasweta; Kim, Haesook T; Chen, Yi-Bin et al. (2018) Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors: Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial. Biol Blood Marrow Transplant 24:2216-2223|
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