The contributory roles of the CXCL12/CXCR4/CXCR7 axis in normal and malignant hematopoiesis: A possible therapeutic target in hematologic malignancies

Eur J Pharmacol. 2022 Apr 5;920:174831. doi: 10.1016/j.ejphar.2022.174831. Epub 2022 Feb 17.

Abstract

C-X-C motif chemokine 12 (CXCL12), also known as stromal cell-derived factor-1 (SDF-1), is produced by the bone marrow microenvironment. This chemokine binds and activates its cognate receptors C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine receptor type 7 (CXCR7) to widely regulate cell proliferation, survival, differentiation, as well as homing and mobilization of hematopoietic stem cells (HSCs) in specialized niches within the bone marrow. Given this key role in hematopoiesis, it comes as no surprise that any aberrancies in CXCL12/CXCR4 or CXCL12/CXCR7 pathways might lead to excessive proliferation of HSCs, an event that leads to the development of leukemia. So far, numerous therapeutic interventions have been developed to harness CXCL12/CXCR4 and CXCL12/CXCR7 axes in leukemic cells. Plerixafor, BKT140, LY2510924, PF-06747143, ulocuplumab, and NOX-A12 are among the most well-known CXCR4 and CXCL12 modulators that their therapeutic efficacies have been evaluated in different pre-clinical and clinical studies of hematologic malignancies. To have an overview of the importance of CXCL12/CXCR4 and CXCL12/CXCR7 axes in the pathogenesis of leukemia and to gather information about the latest advances as well as challenges in targeting these axes in clinical settings, the present review has begun with a discussion about how aberrant expression of CXCL12/CXCR4 and CXCL12/CXCR7 pathways might regulate leukemogenesis and ended by outlining the key news of preclinical and clinical investigations in leukemia treatment.

Keywords: CXCR4; CXCR7; Chemokine CXCL12; Hematologic neoplasms.

Publication types

  • Review

MeSH terms

  • Chemokine CXCL12 / metabolism
  • Hematologic Neoplasms* / drug therapy
  • Hematopoiesis
  • Hematopoietic Stem Cell Mobilization
  • Heterocyclic Compounds*
  • Humans
  • Receptors, CXCR4
  • Signal Transduction
  • Tumor Microenvironment

Substances

  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Heterocyclic Compounds
  • Receptors, CXCR4