CXCR4-SERINE339 regulates cellular adhesion, retention and mobilization, and is a marker for poor prognosis in acute myeloid leukemia

Leukemia. 2014 Mar;28(3):566-76. doi: 10.1038/leu.2013.201. Epub 2013 Jul 2.


The CXCR4 receptor is a major regulator of hematopoietic cell migration. Overexpression of CXCR4 has been associated with poor prognosis in acute myelogenous leukemia (AML). We have previously shown that ligand-mediated phosphorylation of the Serine339 (CXCR4-S339) residue of the intracellular domain by PIM1 is implicated in surface re-expression of this receptor. Here, we report that phosphorylation of CXCR4-S339 in bone marrow (BM) biopsies correlated with poor prognosis in a cohort of AML patients. To functionally address the impact of CXCR4-S339 phosphorylation, we generated cell lines-expressing CXCR4 mutants that mimic constitutive phosphorylation (S339E) or abrogate phosphorylation (S339A). Whereas the expression of CXCR4 significantly increased, both CXCR4-S339E and the CXCR4-S339A mutants significantly reduced the BM homing and engraftment of Kasumi-1 AML cells in immunodeficient mice. In contrast, only expression of the CXCR4-S339E mutant increased the BM retention of the cells and resistance to cytarabine treatment, and impaired detachment capacity and AMD3100-induced mobilization of engrafted leukemic cells. These observations suggest that the poor prognosis in AML patients displaying CXCR4-S339 phosphorylation can be the consequence of an increased retention to the BM associated with an enhanced chemoresistance of leukemic cells. Therefore, CXCR4-S339 phosphorylation could serve as a novel prognostic marker in human AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / chemistry
  • Biomarkers / metabolism*
  • Cell Adhesion / physiology*
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • Middle Aged
  • Mutation
  • Prognosis
  • Receptors, CXCR4 / chemistry
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / physiology*
  • Serine / chemistry*


  • Biomarkers
  • CXCR4 protein, human
  • Receptors, CXCR4
  • Serine