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

Cell Metab. 2019 May 7;29(5):1217-1231.e7. doi: 10.1016/j.cmet.2019.01.011. Epub 2019 Feb 14.


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.

Trial registration: NCT01371981.

Keywords: CRISPR; acute myeloid leukemia; apoptosis; cancer metabolism; genetic screens; heme biosynthesis; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Drug Resistance, Neoplasm*
  • Electron Transport
  • Electron Transport Chain Complex Proteins / metabolism
  • Gene Knockout Techniques
  • HEK293 Cells
  • Heme / biosynthesis*
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Sulfonamides / pharmacology
  • THP-1 Cells
  • Transduction, Genetic


  • Antineoplastic Agents
  • BCL2 protein, human
  • Bridged Bicyclo Compounds, Heterocyclic
  • Electron Transport Chain Complex Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Heme
  • venetoclax

Associated data