Open AccessNuclear NAD + homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells
Author(s) -
Xiangguo Shi,
Yajian Jiang,
Ayumi Kitano,
Tianyuan Hu,
Rebecca Murdaugh,
Yuan Li,
Kevin A. Hoegenauer,
Rui Chen,
Koichi Takahashi,
Daisuke Nakada
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abf3895
Subject(s) - nad+ kinase , stem cell , myeloid leukemia , haematopoiesis , cancer research , leukemia , cancer stem cell , biology , cancer cell , microbiology and biotechnology , cancer , chemistry , biochemistry , immunology , genetics , enzyme
Metabolic dysregulation underlies malignant phenotypes attributed to cancer stem cells, such as unlimited proliferation and differentiation blockade. Here, we demonstrate that NAD + metabolism enables acute myeloid leukemia (AML) to evade apoptosis, another hallmark of cancer stem cells. We integrated whole-genome CRISPR screening and pan-cancer genetic dependency mapping to identify NAMPT and NMNAT1 as AML dependencies governing NAD + biosynthesis. While both NAMPT and NMNAT1 were required for AML, the presence of NAD + precursors bypassed the dependence of AML on NAMPT but not NMNAT1 , pointing to NMNAT1 as a gatekeeper of NAD + biosynthesis. Deletion of NMNAT1 reduced nuclear NAD + , activated p53, and increased venetoclax sensitivity. Conversely, increased NAD + biosynthesis promoted venetoclax resistance. Unlike leukemia stem cells (LSCs) in both murine and human AML xenograft models, NMNAT1 was dispensable for hematopoietic stem cells and hematopoiesis. Our findings identify NMNAT1 as a previously unidentified therapeutic target that maintains NAD + for AML progression and chemoresistance.