Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity.

Published

Journal Article

Crosstalk between metabolic and survival pathways is critical for cellular homeostasis, but the connectivity between these processes remains poorly defined. We used loss-of-function CRISPR/Cas9 knockout screening to identify metabolic genes capable of influencing cellular commitment to apoptosis, using sensitization to the BCL-2 inhibitor ABT-199 in BCL-2-dependent acute myeloid leukemia (AML) cell lines as a proxy for apoptotic disposition. This analysis revealed metabolic pathways that specifically cooperate with BCL-2 to sustain survival. In particular, our analysis singled out heme biosynthesis as an unappreciated apoptosis-modifying pathway. Although heme is broadly incorporated into the proteome, reduction of heme biosynthesis potentiates apoptosis through the loss of ETC activity, resulting in baseline depolarization of the mitochondrial membrane and an increased propensity to undergo apoptosis. Collectively, our findings chart the first apoptotic map of metabolism, motivating the design of metabolically engaged combination chemotherapies and nominating heme biosynthesis as an apoptotic modulator in AML.

Full Text

Duke Authors

Cited Authors

  • Lin, KH; Xie, A; Rutter, JC; Ahn, Y-R; Lloyd-Cowden, JM; Nichols, AG; Soderquist, RS; Koves, TR; Muoio, DM; MacIver, NJ; Lamba, JK; Pardee, TS; McCall, CM; Rizzieri, DA; Wood, KC

Published Date

  • May 7, 2019

Published In

Volume / Issue

  • 29 / 5

Start / End Page

  • 1217 - 1231.e7

PubMed ID

  • 30773463

Pubmed Central ID

  • 30773463

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2019.01.011

Language

  • eng

Conference Location

  • United States