The bone marrow microenvironment and leukemia: biology and therapeutic targeting

Abstract

Multiple studies have demonstrated that interaction with the bone marrow stromal microenvironment contributes to the survival of leukemia cells. One explanation for this phenomenon is the interaction between the cell surface receptors CXCR4 and CXCL12. Through CXCL12/CXCR4-mediated chemotaxis, leukemia cells migrate to microscopic niches within the bone marrow, which leads to increased proliferation and survival. Several studies have suggested that increased CXCR4 expression may portend a poor prognosis in various types of leukemia, possibly due to increased protection of leukemia cells by bone marrow stroma. A potential therapeutic strategy to overcome this stromal-mediated survival advantage is to target CXCR4. Inhibition of CXCR4 may allow leukemia cells to be released from bone marrow niches that confer resistance to chemotherapy and negate the survival benefit imparted by bone marrow stroma.

Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment

“…Most importantly, PP242, but not rapamycin derivative temsirolimus, induced cell death in stromal cocultures, which otherwise reliably support viability of leukemic blasts (supplemental Figure 1) and reduce efficacy of traditional anti-AML chemotherapy agents. 35 These data support the recently reported evidence of the superior antileukemic potency of mTOR kinase inhibitors 36,37 or dual P13K/ mTORK inhibitors 38 through suppression of rapamycin-resistant mTORC1 and mTORC2 complexes compared with allosteric mTOR inhibitors. These findings indicate that mTOR signaling plays an essential role in the stroma-leukemia cell interaction, and its blockade is sufficient to abrogate the stroma-mediated survival advantage of leukemic cells.…”

In Vitro Modeling of Tissue-Specific 3D Microenvironments and Possibile Application to Pediatric Cancer Research

“…Several mechanisms have been proposed to explain this feature, such as the induction of the cell adhesion-mediated drug resistance phenomenon (CAM-DR) [147,148], the induction of a reversible quiescent state, that favors cell survival because most standard chemotherapies act on proliferating cells [145] and the increase of hypoxic areas which contributes to chemoresistance of leukemic cells http: //www.ncbi.nlm.nih.gov/pmc/ articles/PMC3414410/ -R10 [149]. The discovery of this complex network, in which the leukemic cells are only one of the participating players, suggests that more effective molecular therapies should target not only leukemic cells but also their microenvironment [150,151]. Thus, useful leukemia models should reproduce not only a generic 3D environment, but also the specific leukemia microenvironment, represented by BMSCs, specific components of ECM or soluble factors embedded.…”

Roles of Rho GTPases in leucocyte and leukaemia cell transendothelial migration

“…This leads to rapid recruitment of leucocytes into inflamed tissues. Leukaemia cells proliferate in niches in the bone marrow and/or lymph nodes, and therefore need to adhere to and cross the endothelium to enter these sites [21][22][23].…”