Inhibition of UBE2N as a Therapeutic Approach in MDS and AML
Pharmacologic and genetic inhibition of UBE2N suppresses the function and viability of MDS/AML cells lines and patient samples. A commercially available compound has been identified.
Hematopoietic stem and progenitor cells (HSPC) from myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients exhibit overexpression of TRAF6, suggesting a dependency of leukemic HSPC on activated innate immune signaling. Unfortunately, inhibiting TRAF6 directly has proven difficult. UBE2N is a ubiquitin-conjugating E2 enzyme that catalyzes lysine 63 linked ubiquitin chains on TRAF6 and its substrates. Treatment of MDS/AML cell lines with a UBE2N inhibitor reduced cellular metabolic activity, induced a G2/M cell cycle arrest, and increased cell death. The compound inhibited tumor growth by 50-70% of MDS xenotransplanted patient derived cell line. Studies have shown that pharmacologic or genetic inhibition of UBE2N in combination with lenalidomide (LEN) significantly suppresses the function and viability of MDS/AML cell lines and patient samples in vitro, even for MDS/AML cells that are refractory to LEN alone. While LEN has shown encouraging results in del(5q) MDS patients, its effects are limited in other cytogenetic subtypes of MDS or AML. Therefore, UBE2N is a promising target to extend the use of LEN to other subtypes of MDS/AML, and inhibition of UBE2N alone or in combination with LEN is a promising therapeutic approach for MDS and AML.
- Reduced clonogenic capacity of MDS/AML cell lines and primary cells, without significantly affecting normal HSPC.
- Inhibition of UBE2N can extend the use of LEN to other subtypes of MDS/AML.
Over 20K new cases of AML and 15K-20K new cases of MDS in the U.S. annually. About 1/3 of patients with MDS progress to AML.
Daniel Starczynowski, PhD; Laura Barreyro, PhD, Division of Experimental Hematology & Cancer Biology; William Seibel, PhD, Division of Oncology