Myeloid malignancies and the microenvironment

Abstract

Research in the last few years has revealed a sophisticated interaction network between multiple bone marrow cells that regulate different hematopoietic stem cell (HSC) properties such as proliferation, differentiation, localization, and self-renewal during homeostasis. These mechanisms are essential to keep the physiological HSC numbers in check and interfere with malignant progression. In addition to the identification of multiple mutations and chromosomal aberrations driving the progression of myeloid malignancies, alterations in the niche compartment recently gained attention for contributing to disease progression. Leukemic cells can remodel the niche into a permissive environment favoring leukemic stem cell expansion over normal HSC maintenance, and evidence is accumulating that certain niche alterations can even induce leukemic transformation. Relapse after chemotherapy is still a major challenge during treatment of myeloid malignancies, and cure is only rarely achieved. Recent progress in understanding the niche-imposed chemoresistance mechanisms will likely contribute to the improvement of current therapeutic strategies. This article discusses the role of different niche cells and their stage- and disease-specific roles during progression of myeloid malignancies and in response to chemotherapy.

Figure 1.

Role of BM blood vessels in myeloid malignancies. Angiogenesis increases during progression of myeloid malignancies and is particularly associated with fibrotic stages of the disease. Leukemic cells produce angiogenic factors such as VEGF and inflammatory cytokines (blue arrows) to stimulate proliferation of ECs, expression of adhesion molecules, and secretion of angiocrine factors. EC-derived angiocrine factors (red arrows) stimulate leukemic cell proliferation and survival, triggering a vicious cycle to remodel the BM into a self-reinforcing niche. OB, osteoblast.

Figure 2.

Microenvironmental changes during leukemogenesis. In the BM niche, HSC function is tightly controlled by a specialized microenvironment comprising sympathetic neurons, BMSCs, OBs, and ECs. (A) During early stages of myeloid malignancies, HSPCs acquire genetic alterations that transform them into LSCs. These mutations also create a proinflammatory environment that damages sensitive elements of the microenvironment, such as Schwann cells and their associated nerve terminals. (B) During intermediate stages of the disease, the environment remodels into a self-reinforcing niche that interferes with normal hematopoiesis. LSCs become independent of niche signals and localize more centrally in the BM. MSCs acquire an abnormal phenotype, and angiogenesis increases as a result of high VEGF and cytokine levels. (C) Late stages of the disease are characterized by a proinflammatory environment and myelofibrosis, high blood vessel density, and central LSC localization. Rarγ, retinoic acid receptor γ; Rb, retinoblastoma protein; TPO, thrombopoeitin.

Figure 3.

Protection of LSCs from chemotherapy by the microenvironment. Chemotherapy eradicates LSCs but at the same time damages multiple cell types of the niche and triggers subsequent niche regeneration. Prolonged treatment induces the development of resistance mechanisms, some of which are mediated by niche cells, including BMSCs and ECs. MT, mitochondria; FN, fibronectin.