Our broad long-term objectives are to delineate the cellular and molecular mechanisms by which genetic changes cooperate to transform myeloid progenitors into acute myeloid leukemia (AML). Acute promyelocytic leukemia (APL), one sub-type of AML, is associated with a chromosomal translocation that fuses the retinoic acid receptor alpha gene (RARA) with the gene encoding the PML nuclear protein. We expressed PML-RAR1 in myeloid cells of mice to generate a mouse model of APL. This model in combination with studies of human APL cells can be used to address central questions in leukemia biology including (i) what cells can accumulate genetic changes such that they become leukemia? (ii) how do initiating events alter cellular behavior? (iii) how do cooperating events further propel cells towards transformation? (iv) once a malignancy has formed, from what cells can the leukemia re-grow after treatment? The specific aims of this proposal are: (1) Identify mechanisms by which PML-RAR1 contributes to leukemia and response to therapy, (2) Characterize the myeloid cells that serve as leukemic stem cells (LSC) in APL and identify mechanisms by which the proliferative potential of these cells is expanded, (3) Illuminate how a common genetic change in human APL, gain of chromosome 8, cooperates with PML- RAR1 in leukemic transformation.
For Aim 1, we will assess how various PML-RAR1 related alleles influence proliferative potential and cooperate in leukemic transformation. We will also generate mice carrying an inducible allele of activated FLT3: we will characterize the effects of activating this allele in the presence of PML-RAR1 or variants, and will use this system in combination with studies of human APL cells to identify key transcriptional targets of PML-RAR1.
For Aim 2, we will characterize the cells that can transplant disease in our mouse APL model, identify LSC for human APL, and delineate myeloid cells that can be converted to leukemia. We will also assess the impact of environment and therapy on LSC. Further, we will identify genes whose alteration can cooperate with PML-RAR1 to enhance self-renewal of myeloid progenitors.
For Aim 3, we will delineate mechanisms through which MYC and TRIB1 (encoded on human chromosome 8) can contribute to APL and assess the potential for targeting MYC therapeutically in AML.
Acute myeloid leukemia will be diagnosed in approximately 12,000 Americans this year and, despite improvements in treatment, more than 9,000 will die as a result of their disease. The proposal seeks to understand how genetic changes combine to cause leukemia. The results of the proposed studies should help us to understand acute myeloid leukemia and thereby should aid the development of new treatments for leukemias and other cancers.
|Voisset, Edwige; Moravcsik, Eva; Stratford, Eva W et al. (2018) Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice. Blood 131:636-648|
|Gaillard, Coline; Surianarayanan, Sangeetha; Bentley, Trevor et al. (2018) Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia. Blood Adv 2:2462-2466|
|Keeshan, Karen; Vieugué, Pauline; Chaudhury, Shahzya et al. (2016) Co-operative leukemogenesis in acute myeloid leukemia and acute promyelocytic leukemia reveals C/EBP? as a common target of TRIB1 and PML/RARA. Haematologica 101:1228-1236|
|Gaillard, Coline; Tokuyasu, Taku A; Rosen, Galit et al. (2015) Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation. Haematologica 100:1064-75|
|Brondfield, Sam; Umesh, Sushma; Corella, Alexandra et al. (2015) Direct and indirect targeting of MYC to treat acute myeloid leukemia. Cancer Chemother Pharmacol 76:35-46|
|Smith, Catherine Choy; Lasater, Elisabeth A; Lin, Kimberly C et al. (2014) Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci U S A 111:5319-24|
|Omidvar, Nader; Maunakea, Mei Lin; Jones, Letetia et al. (2013) PML-RARýý co-operates with Sox4 in acute myeloid leukemia development in mice. Haematologica 98:424-7|
|Choi, Grace; Huang, Brian; Pinarbasi, Emile et al. (2012) Genetically mediated Nf1 loss in mice promotes diverse radiation-induced tumors modeling second malignant neoplasms. Cancer Res 72:6425-34|
|Huang, Ying; Hou, Jia-Kai; Chen, Ting-Ting et al. (2011) PML-RAR? enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway. Autophagy 7:1132-44|
|Scaglioni, Pier Paolo; Cai, Lu Fan; Majid, Samia M et al. (2011) Treatment with 5-azacytidine accelerates acute promyelocytic leukemia leukemogenesis in a transgenic mouse model. Genes Cancer 2:160-5|
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