G-CSF-dependent de-/acetylation of myeloid-specific transcription factors LEF 1 and C/EBPalpha in myeloid differentiation and leukemogenesis

• Applicant: Professorin Dr. Julia Skokowa, Ph.D.
• Subject Area: Hematology, Oncology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 247949958

G-CSF is a major regulator of granulopoiesis, inducing proliferation and differentiation of hematopoietic stem cells toward granulocytes and monocytes. Failures in G-CSFR signaling are causative for two hematological disorders: severe congenital neutropenia (CN) and AML. In CN patients, myeloid progenitor cells failed to differentiate into granulocytes. In AML, hematopoietic stem cells loose the ability to differentiate and show uncontrolled proliferation. More than 90% of CN patients respond to high pharmacological doses of G-CSF (up to 80 mcg/kg/day). CN is a pre-leukemic syndrome, ca. 25% of patients develop AML. Eighty percent of CN/AML patients have acquired G-CSFR mutations, assuming the involvement of G-CSFR signaling in leukemogenesis. Post-translational modification of proteins by de-/acetylation is important for their functions, but is still poorly investigated. It is also unclear, whether G-CSFR-triggered myeloid differentiation requires de-/acetylation of myeloid-specific signaling proteins. The analysis of the de-/acetylation of transcription factors in CN, CN/AML and de novo AML patients in comparison to healthy individuals may help to delineate new signaling systems operating during myeloid differentiation or leukemogenesis. We aim: (1) to investigate the role of de-/acetylation of myeloid-specific transcription factors LEF-1 and its target C/EBPalpha in myeloid differentiation and leukemogenic transformation; (2) to analyse the role of G-CSFR/NAMPT/NAD+/SIRT system in the de-/acetylation of LEF-1 and C/EBPalpha (3) to analyse the effects of de-/acetylation of LEF-1 for its nuclear translocation by interaction with the HCLS1 protein. We hope that by modulation of de-/acetylation status of LEF-1 and C/EBPalpha proteins using pharmacological modulators of NAMPT/SIRT signalling, we will be able to regulate LEF-1/C/EBPalpha-triggered myeloid differentiation and leukemogenic transformation, which could be used for treatment of neutropenia or myeloid leukemia.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Karl Welte