The bone marrow microenvironment as a sanctuary for minimal residual disease in CML

Abstract

Bcr-abl kinase inhibitors have provided proof of principal that targeted therapy holds great promise for the treatment of cancer. However, despite the success of these agents in treating chronic myelogenous leukemia (CML), the majority of patients continue to present with minimal residual disease contained within the bone marrow microenvironment. These clinical observations suggest that the bone marrow microenvironment may provide survival signals that contribute to the failure to eliminate minimal residual disease. The bone marrow microenvironment is comprised of multiple sub-domains which vary in cellular composition and gradients of soluble factors and matrix composition. Experimental evidence indicate that exposure of tumor cells to either bone marrow derived soluble factors or the extracellular matrix can confer a multi-drug resistance phenotype. Together, these data indicate that targeting such pathways may be a viable approach for increasing the efficacy of chemotherapy. Moreover, we propose that personalized medicine must go beyond understanding predictive models inherent to tumors but rather build predictive models that consider diversity in response due to interactions with the tumor microenvironment. Although review will focus on CML, understanding the contribution of the bone marrow microenvironment could contribute to rationale combination therapy in other types of leukemia, multiple myeloma and solid tumors which metastasize to the bone.

Fig. 1

Schematic representation of the molecular interactions between hematopoietic stem cells and their niches in the bone marrow. In normal physiological conditions, the hematopoietic stem cells (HSCs) reside either at the endosteum, lodged with the osteoblasts (OBT) (osteoblastic niche) or at the sinusoidal vessels (SV) (vascular niche). The osteoblastic niche provides the microenvironment for HSC maintenance and quiescence and the vascular niche provides the microenvironment for HSC prolirferation and differentiation. The oxygen and the calcium gradient might play a crucial role in maintenance of the different niches within the bone marrow.

Fig. 2

Schematic representation of the mechanism for the stroma-mediated resistance in the bone marrow. The tumor cells within the bone marrow (BM) is bathed in a mileu of cytokines (IL-6, IL-11, IL-1, TNF-α, IFNs) growth factors (VEGF, FGF, G-CSF, GM-CSF, TGFs) and chemokine factors (SCF, SDF-1) secreted by the BM stromal cells (paracrine) or the tumor cells (autocrine). In addition, the tumor cells interact with the stromal compartment with the help of integrins (VLA-4, ICAM, VCAM) and N-cadherins. All this interactions culminates in the activation of signaling pathways (MAPK, JAK/STAT, PI3K-Akt) within the tumor cells which ultimately leads to the proliferation and survival of the tumor cell in the BM stroma.