Chemosensitivity is differentially regulated by the SDF-1/CXCR4 and SDF-1/CXCR7 axes in acute lymphoblastic leukemia with MLL gene rearrangements. (December 2018)

• Record Type: Journal Article
• Authors: Ando, Norie; Furuichi, Yoshiyuki; Kasai, Shin; Tamai, Minori; Harama, Daisuke; Kagami, Keiko; Abe, Masako; Goi, Kumiko; Inukai, Takeshi; Sugita, Kanji
• Is Part Of: Leukemia research. Volume 75(2018)
• Page Start: 36
• Page End: 44
• Publication Date: 2018-12
• Subjects: Acute lymphoblastic leukemia -- Mixed-lineage leukemia gene -- SDF-1 -- CXCR4 -- CXCR7 -- Chemosensitivity; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2018.11.001
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: MLL +ALL cells expressed CXCR4 and CXCR7, both receptors for SDF-1. CXCR4 inhibitor AMD3100 significantly inhibited Ara-C-induced apoptosis. CXCR7 inhibitor CCX733 significantly enhanced Ara-C-induced apoptosis. Differential roles of the SDF-1/CXCR4 and SDF-1/CXCR7 axes for determining Ara-C sensitivity was discussed. Abstract: Although recent advances in chemotherapy have markedly improved outcome of acute lymphoblastic leukemia (ALL), infantile ALL with MLL gene rearrangements ( MLL +ALL) is refractory to chemotherapy. We have shown that specific cytokines FLT3 ligand and TGFβ1 both of which are produced from bone marrow stromal cells synergistically induced MLL +ALL cells into chemo-resistant quiescence, and that treatment of MLL +ALL cells with inhibitors against FLT3 and/or TGFβ1 receptor partially but significantly converts them toward chemo-sensitive. In the present study, we showed that MLL +ALL cells expressed CXCR4 and CXCR7, both receptors for the same chemokine stromal cell derived factor-1 (SDF-1), but their biological events were differentially regulated by the SDF-1/CXCR4 and SDF-1/CXCR7 axes and particularly exerted an opposite effect for determining chemo-sensitivity of MLL +ALL cells; enhancement via the SDF-1/CXCR4 axis vs. suppression via the SDF-1/CXCR7 axis. Because cytosine-arabinoside-induced apoptosis of MLL +ALL cells was inhibited by pretreatment with the CXCR4 inhibitor but rather accelerated by pretreatment with the CXCR7 inhibitor, an application of the CXCR7 inhibitor may become a good treatment option in future for MLL +ALL patients. MLL +ALL has a unique gene profile distinguishable from other types of ALL and AML, and should be investigated separately in responses to biological active agents including chemokine inhibitors.