title: CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model.
abstract: The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates in pathogenesis is unclear. Here, we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4 (high) from CXCR4(neg/low) AML patients. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOD/Shi-scid/IL-2Rγ(null) (NOG) leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to chemokine CXC motif ligand 12 (CXCL12). Functional analysis showed a greater mobilization of leukemic cells and LICs in response to drugs, suggesting that they target the interaction between leukemic cells and their supportive bone marrow microenvironment. In addition, increased apoptosis of leukemic cells in vitro and in vivo was observed. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1009, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: H
authors.initials: H
authors.lastname: Abdelouahab
authors.forename: M
authors.initials: M
authors.lastname: Wittner
authors.forename: C
authors.initials: C
authors.lastname: Willekens
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.forename: A
authors.initials: A
authors.lastname: Betems
authors.forename: V
authors.initials: V
authors.lastname: Joulin
authors.forename: P
authors.initials: P
authors.lastname: Opolon
authors.forename: O
authors.initials: O
authors.lastname: Bawa
authors.forename: F
authors.initials: F
authors.lastname: Pasquier
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: N
authors.initials: N
authors.lastname: Fujii
authors.forename: P
authors.initials: P
authors.lastname: Gonin
authors.forename: E
authors.initials: E
authors.lastname: Solary
authors.forename: W
authors.initials: W
authors.lastname: Vainchenker
authors.forename: P
authors.initials: P
authors.lastname: Coppo
authors.forename: S
authors.initials: S
authors.lastname: De Botton
authors.forename: F
authors.initials: F
authors.lastname: Louache
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000378:metabolism; D002675:Child, Preschool; D000080027:Cyclams; D004195:Disease Models, Animal; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor