3013 – LEDGF/P75 PLAYS OPPOSING ROLES IN CHEMORESISTANCE IN DIFFERENT LEUKEMIAS

Abstract

Lens Epithelium Derived Growth Factor/p75 (LEDGF/p75) is a chromatin-associated protein involved in multiple malignancies. It tethers the MLL/KMT2A fusion protein to the chromatin and plays a critical role in the initiation and maintenance of MLL-r leukemia which mostly affects pediatric patients and is linked to a high rate of relapse and resistance to conventional chemotherapy. Moreover, LEDGF/p75 is overexpressed in AML and prostate cancer patients who are resistant to chemotherapy. We have previously shown that reduced LEDGF/p75 expression sensitizes proliferation and survival of KMT2A-r Thp1 cells to cytarabine treatment through the sphingosine-1 pathway. Here, we studied modulation of chemoresistance by LEDGF/p75 in various types of leukemia. At first, we corroborated the results in Thp1 and expanded these findings by ectopically expressing LEDGF/p75 in the KMT2A-r Molm13 cells that naturally express low levels of LEDGF/p75. Overexpression of LEDGF/p75 in those cells resulted in increased proliferation and reduced apoptosis in the presence of cytarabine. A similar result was obtained after LEDGF/p75 depletion in K562 (CML, KMT2A WT) since a 3-fold increase in sensitivity to vincristine compared to the control was found. Vincristine treated K562 LEDGF/p75 KD cells show more apoptosis and increased caspase3 expression. Interestingly, LEDGF/p75 depletion in SEM cells (ALL, KMT2A-r) resulted in 4-fold more proliferation and less apoptosis upon cytarabine treatment compared to cells expressing mock miRNA. In conclusion, LEDGF/p75 induces chemoresistance in Thp1 and K562 cells to cytarabine and vincristine respectively but sensitizes SEM cells to cytarabine. Our findings highlight the opposing role of LEDGF/p75 in modulating chemoresistance across leukemias. Targeting LEDGF/p75 may be a promising strategy to enhance chemotherapy efficacy in specific leukemic subtypes.