Daisuke Nakada, Ph.D.
2020 Funding recipient
NAD+ metabolism governed by NMNAT1 regulates venetoclax sensitivity in MDS
Discovery Research Grant 2020
MDS is a heterogeneous hematological disorder characterized by insufficient production of blood cells and frequent progression into acute myeloid leukemia. Many mutations have been found in MDS, contributing to the heterogeneous nature of the disease and making cure a challenge. The current frontline therapy Azacitidine has improved the survival of MDS patients, but patients that do not respond to Azacitidine monotherapy have poor prognosis with no options for second-line therapy. Recent clinical trials in acute myeloid leukemia have shown that combining another drug called Venetoclax together with Azacitidine improves the outcome of the therapy, and new trials are ongoing to test the efficacy of Venetoclax therapy for MDS. However, Venetoclax has some side effects such as neutropenia, which may complicate the therapy of elderly MDS patients. Identifying mechanisms that make MDS more sensitive to Venetoclax therapy may lead to novel combination therapies with low dose of Venetoclax to mitigate side effects while augmenting the effectiveness of Venetoclax against MDS.
To identify new genes that may regulate Venetoclax sensitivity, we combined two approaches; data mining of publicly available dataset of drug sensitivity of cancer cells and our own gene discovery experiments. This led to the key insight that a metabolite called NAD+ promotes resistance against Venetoclax, and that one gene named NMNAT1 is the essential regulator of NAD+ production. To study how NMNAT1 regulates the sensitivity of MDS cells to Venetoclax, we generated a mouse model of MDS that lacks the NMNAT1 gene.
The results from our study will provide key preclinical evidence that inhibiting NAD+ metabolism of MDS sensitizes MDS to Venetoclax.