Nuclear NAD ⁺ homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells

Abstract

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.

NMNAT promotes glioma growth through regulating post-translational modifications of P53 to inhibit apoptosis

“…During the submission of this manuscript, two groups reported the distinct roles of NMNAT1 and NMNAT2 in acute myeloid leukemia and ovarian cancer respectively ( Challa et al, 2021 ; Shi et al, 2021 ). Shi et al, 2021 showed that NMNAT1-mediated NAD + metabolism regulates p53 acetylation and enables acute myeloid leukemia (AML) to evade apoptosis ( Shi et al, 2021 ).…”

“…During the submission of this manuscript, two groups reported the distinct roles of NMNAT1 and NMNAT2 in acute myeloid leukemia and ovarian cancer respectively ( Challa et al, 2021 ; Shi et al, 2021 ). Shi et al, 2021 showed that NMNAT1-mediated NAD + metabolism regulates p53 acetylation and enables acute myeloid leukemia (AML) to evade apoptosis ( Shi et al, 2021 ). Challa et al, 2021 showed that NMNAT2-mediated cytosolic NAD + synthesis regulates ribosome ADP-ribosylation to maintain protein homeostasis in ovarian cancer ( Challa et al, 2021 ).…”

BH3 Mimetics in Hematologic Malignancies

“…Likewise, the absence of BAX or NOXA (PMAIP1), overexpression of BCL-XL or MCL1, and mutation of TP53 all impart venetoclax resistance [106,107]. Other mechanisms of venetoclax resistance in AML include disrupted mitochondrial homeostasis with increased OxPhos as a result of upregulated amino acid and/or fatty acid oxidation [108,109]. In MCL, venetoclax resistance is also predominantly associated with non-BCL2 gene alterations including TP53, CDKN2A, KMT2C/D, SMARCA4, or NOTCH2 [110].…”

The key role of the NAD biosynthetic enzyme nicotinamide mononucleotide adenylyltransferase in regulating cell functions

“…In the nucleus, NMNAT1 provides NAD to sirtuins and PARP1 regulating their activities. [10][11][12] NMNAT2 is anchored to the membranes of the Golgi apparatus and contributes to maintain NAD levels in the cytosol where it functionally interacts with PARP6. 13 Within mitochondria, NMNAT3 provides NAD to mitochondrial ARTs 14 and SIRT3, 15 whereas in endolysosomes it contributes with CD38 to NAADP generation 16 generated that suggest a topology highly similar to the other isoforms and revealed an isoform-specific domain of about 60 residues, which is dispensable for the catalytic activity and essential for anchoring the enzyme to the Golgi membrane via palmitoylation of two adjacent cysteine residues.…”

“…Experiments in mice confirmed the NMNAT1 requirement for leukemogenesis, so identifying NMNAT1 as a promising therapeutic target for AML. 10 Recent studies report on NMNAT2 deregulation in cancer and provide evidence of its involvement in tumor progression. In particular, NMNAT2 levels increase in colorectal cancer, with a positive correlation with tumor invasiveness and stage.…”