CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia

Cell Rep. 2020 May 26;31(8):107684. doi: 10.1016/j.celrep.2020.107684.


Acute myeloid leukemia (AML) is defined by an accumulation of immature myeloid blasts in the bone marrow. To identify key dependencies of AML stem cells in vivo, here we use a CRISPR-Cas9 screen targeting cell surface genes in a syngeneic MLL-AF9 AML mouse model and show that CXCR4 is a top cell surface regulator of AML cell growth and survival. Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow. In contrast, the CXCR4 ligand CXCL12 is dispensable for leukemia development in recipient mice. Moreover, expression of mutated Cxcr4 variants reveals that CXCR4 signaling is essential for leukemia cells. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. Taken together, our results identify CXCR4 signaling as essential for AML stem cells by protecting them from differentiation independent of CXCL12 stimulation.

Keywords: CRISPR; CXCL12; CXCR4; CXCR4 signaling; ROS; acute myeloid leukemia; differentiation; leukemia stem cell; oxidative stress; screen.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Chemokine CXCL12 / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Oncogene Proteins, Fusion / metabolism*
  • Oxidative Stress
  • Reactive Oxygen Species
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction


  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • MLL-AF9 fusion protein, mouse
  • Oncogene Proteins, Fusion
  • Reactive Oxygen Species
  • Receptors, CXCR4