Histone demethylases KDM7 in hematopoiesis and leukemogenesis

• Applicant: Maria Francisca Arteaga-Paz, Ph.D.
• Subject Area: Hematology, Oncology
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269219419

Histone modifications largely contribute to normal hematopoiesis and leukemogenesis of acute myeloid leukemia (AML). However, the significance of most of the changes in histone methylation and acetylation patterns as well as the underlying mechanisms still largely remains unknown. For the KDM7 family subgroup of Histone Lysine Demethylases (KDMs), namely PHF2, PHF8 and KIAA1718, functions in both normal hematopoiesis and leukemogenesis are assumed as well. For PHF8 we recently identified a key role in mediation of response to all-trans retinoid acid (ATRA) treatment in acute promyelocytic leukemia (APL). Preliminary work from our group now revealed that high expression levels of PHF8 correlate with improved overall survival of AML patients among all subtypes, strongly suggesting that the role of PHF8 in AML is not solely limited to APL. The three members of the KDM7 family show strong structural homology in terms of their functional domains. Thus, in this project we are going to assess the mechanisms of action of the KDM7 subfamily in normal hematopoietic stem cells and during differentiation of hematopoietic cells. For this purpose, we will induce specific and functional gene knockout of PHF2, PHF8 and KIAA1718 in murine hematopoietic progenitor cells by genome editing using the CRISPR/Cas9 technology. Moreover, we are going to determine the role of the KDM7 family in AML leukemogenesis with specific focus on MLL rearranged AML. We will perform colony formation assays, structure function analyses as well as whole genome sequencing of primary AML patient samples. Finally, we will study the option of sensitization of leukemic cells expressing different AML associated oncogenes to ATRA treatment via activation of PHF8. Overall this project will dissect the functions of this novel group of KDMs, in normal hematopoiesis and AML leukemogenesis, and assess the potential role of PHF8 for sensitization of retinoid acid resistant AML cells to the treatment.

• DFG Programme: Research Grants