Regulation of apoptosis by MCL-1 phosphorylation in hematopoiesis and lymphoma

• Applicant: Privatdozent Dr. Ulrich Maurer
• Subject Area: Immunology
• Term: from 2007 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 54617017

MCL-1 has been shown to maintain hematopoietic cell survival. We previously demonstrated that the GSK-3 phosphorylation-deficient mutant, MCL-1S159A, exhibits increased protein stability. Employing adoptive transfer of bone marrow (BM) cells, which had been retrovirally transduced to express MCL-1wt or MCL-1S159A, we found that the numbers of neutrophil granulocytes and lymphocytes as well as the total amount of white blood cells (WBC) were elevated in mice expressing MCL-1S159A. Importantly, expression of MCL-1S159A in Eμ-myc BM cells followed by adoptive transfer accelerated lymphoma significantly more than did expression of MCL-1wt. In the continuation of this study, we will now investigate the survival of BM cells, B-cells, thymocytes and granulocytes from mice expression MCL-1wt vs. MCL-1S159A in ex vivo assays. We will perform BM competition experiments by introducing BM cells expressing MCL-1-IRES-GFP and MCL-1S159A-IRESmCherry in the same recipient mice. As MCL-1 constitutes a major threshold for treatment with novel BH3 mimetics, we will explore whether loss of MCL-1 stability by administration of PI3K inhibitory molecules along with ABT-737 to Eμ-myc mice relieves the resistance to this drug in vivo. We will further investigate whether phosphorylation-deficient MCL-1 exhibits enhanced antiapoptotic activity beyond increased stability, such as increased affinity for BH3-only proteins.

• DFG Programme: Research Grants