The bone marrow microenvironment as a mediator of chemoresistance in acute lymphoblastic leukemia.

Lauren K Meyer,Michelle L Hermiston

doi:10.20517/cdr.2019.63

Abstract

Acute lymphoblastic leukemia (ALL) is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations. With the introduction of intensive multi-agent chemotherapeutic regimens, survival rates for ALL have improved dramatically over the past several decades, though survival rates for adult ALL continue to lag behind those of pediatric ALL. Resistance to chemotherapy remains a significant obstacle in the treatment of ALL, and chemoresistance due to molecular alterations within ALL cells have been described. In addition to these cell-intrinsic factors, the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance, and it is now known that stromal cells within the bone marrow microenvironment, through direct cell-cell interactions and through the release of lymphoid-acting soluble factors, contribute to ALL pathogenesis and chemoresistance. This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context.

Highlights

Acute lymphoblastic leukemia (ALL) is a malignancy of immature lymphoid cells of either the B-cell (B-ALL) or T-cell (T-ALL) lineage
The authors went on to express mutant alleles of IL-7 receptor (IL-7R) pathway genes in glucocorticoid sensitive T-ALL cell lines and found that many of these mutations were sufficient to confer resistance to glucocorticoids, but not to other chemotherapies. Consistent with this idea, we previously demonstrated that IL-7-induced glucocorticoid resistance most commonly occurs in T-ALLs that lack activating mutations in the IL-7R/JAK/STAT5 pathway, and that this resistance phenotype is enriched in T-ALLs of the early T-cell precursor (ETP) subset, which correspond to the early double negative (DN) stages of thymocyte development
Similar to T-ALL, we previously demonstrated that cytokine receptor-like factor 2 (CRLF2)-rearranged Philadelphia chromosome-like (Ph-like) B-ALL samples uniformly demonstrate in vitro glucocorticoid resistance[89]

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is a malignancy of immature lymphoid cells of either the B-cell (B-ALL) or T-cell (T-ALL) lineage. Upon engagement by extracellular stimuli, activated integrins mediate a variety of signal transduction events leading to modulation of a wide range of cellular processes, including cell survival, gene expression, and cell motility[17].

Results

Conclusion