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Chemosensitivity is differentially regulated by the SDF-1/CXCR4 and SDF-1/CXCR7 axes in acute lymphoblastic leukemia with MLL gene rearrangements.
- Source :
-
Leukemia research [Leuk Res] 2018 Dec; Vol. 75, pp. 36-44. Date of Electronic Publication: 2018 Nov 03. - Publication Year :
- 2018
-
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.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Antineoplastic Agents pharmacology
Apoptosis drug effects
Cell Line, Tumor
Chemokine CXCL12 metabolism
Cytarabine pharmacology
Gene Rearrangement
Humans
Receptors, CXCR metabolism
Receptors, CXCR4 metabolism
Drug Resistance, Neoplasm genetics
Histone-Lysine N-Methyltransferase genetics
Myeloid-Lymphoid Leukemia Protein genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5835
- Volume :
- 75
- Database :
- MEDLINE
- Journal :
- Leukemia research
- Publication Type :
- Academic Journal
- Accession number :
- 30453100
- Full Text :
- https://doi.org/10.1016/j.leukres.2018.11.001