This proposal will study the role of the transcription factor Prdm16 in the maintenance of leukemic stem cells (LSCs), specifically in acute myelogenous leukemia (AML). LSCs have the ability to self-renew, but unlike normal blood progenitors, they incompletely differentiate and instead develop into immature blast cells. The mechanisms behind this are unclear. Failure to eliminate LSCs during chemotherapy is likely a primary cause of relapse, and removal of these cells may be necessary and sufficient to treat leukemia. Prdm16 is a transcription factor that plays an important role in the maintenance of hematopoietic stem cells (HSCs). It contains an N-terminal PR methyltransferase domain, whose presence or absence defines two distinct isotypes - f-Prdm16, the full-length form of the protein, and s-Prdm16, which lacks the PR domain. Evidence suggests that s-Prdm16, or similarly, a deletion of the PR domain, may play a role in the development of leukemia. The goal of this proposal is to determine the role of Prdm16 in LSC maintenance. Preliminary data has shown that Prdm16 deletion affects the development of leukemia in an MLL-AF9 model of AML in leukemia derived specifically from HSCs. MLL-AF9 leukemias derived from granulocyte-macrophage progenitors (GMPs) have been shown to have different properties than HSC-derived leukemias, with GMP-derived leukemias being less aggressive and having longer disease latency. Because Prdm16 is highly expressed in HSCs and is not detectable in GMPs, this research proposal will compare the role of Prdm16 in HSC- and GMP-derived leukemias, with the hypothesis that Prdm16 will affect leukemogenicity in HSC, but not GMP-derived AML. This proposal will also use conditional mouse deletion models to determine the stage at which Prdm16 is required for leukemogenesis in this model. Studies from HSCs suggest that Prdm16 will not be required for the homing or engraftment of cells, but rather initiation and propagation of LSCs, which would also more in line with a role for Prdm16 in LSC maintenance. Finally, this proposal will contrast the role of f-Prdm16 and s-Prdm16 in MLL-AF9 leukemia. These isoforms will be expressed individually in Prdm16+/+ and Prdm16-/- leukemic cells and their effect on leukemogenesis will be determined. It is predicted that s-Prdm16 will restore leukemogenicity of Prdm16-/- cells and enhance the leukemogenicity of Prdm16+/+ cells, whereas f-Prdm16 will not, and may even have the opposite effect. This proposal possesses clinical relevance, as the subsets of leukemia associated with Prdm16 have poor to intermediate outcomes in a clinical setting. Furthermore, additional members of the PR family of proteins have been shown to be associated with leukemia, so a more complete understanding of the role of Prdm16 in leukemia may yield further insights into a general mechanism of leukemogenesis established by these proteins.
The proposed research will conduct novel studies on the role of the transcription factor Prdm16 in leukemia, using acute myelogenous leukemia (AML) as the primary model. Specifically, the differential roles of the long and short isoforms of this protein will be explored, with the hypothesis that the short form may function as an oncogene and that the long form may function as a tumor suppressor. This would represent an entirely novel concept in the field of leukemia, and may yield insight into potential therapeutic targets and treatments.
|Corrigan, David J; Luchsinger, Larry L; Justino de Almeida, Mariana et al. (2018) PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature. J Clin Invest 128:3250-3264|
|Luchsinger, Larry L; de Almeida, Mariana Justino; Corrigan, David J et al. (2016) Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature 529:528-31|