From the niche to malignant hematopoiesis and back: reciprocal interactions between leukemia and the bone marrow microenvironment

Abstract

The bone marrow microenvironment (BMME) regulates hematopoiesis through a complex network of cellular and molecular components. Hematologic malignancies reside within, and extensively interact with, the same BMME. These interactions consequently alter both malignant and benign hematopoiesis in multiple ways, and can encompass initiation of malignancy, support of malignant progression, resistance to chemotherapy, and loss of normal hematopoiesis. Herein, we will review supporting studies for interactions of the BMME with hematologic malignancies and discuss challenges still facing this exciting field of research. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Keywords: AGING; BONE; CANCER; CHEMOTHERAPY; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL (HSC) NICHE; INFLAMMATION; LEUKEMIA; MICROENVIRONMENT.

Fig. 1

Malignant cells interact with the BMME at the HSC niche: HSC niches in the BM are endosteal and perivascular. The bone surface is covered with osteoblastic lineage cells, including OBs and osteoclasts. Arterioles (cross‐sectional view) and sympathetic nerves are the site of the arteriolar niche, spatially located with Nestin‐GFP^hi MSCs and NG2⁺ pericytes, which secrete factors for HSC maintenance such as SCF. Closer to the center of the BM are sinusoids (cross‐sectional view), where a sinusoidal HSC niche is comprised of CAR/LepR⁺ cells, Nestin‐GFP^‐lo MSCs, perivascular fibroblasts/NG2+ pericytes, and megakaryocytes. HSCs, LSCs, and progeny extravasate through the sinusoids to circulation for hematopoiesis. HSCs adhere at the niche, and this maintains quiescent reserve HSCs and provides signals for self‐renewal. During malignancy: (i) LSCs can occupy the niche, by adhering to E‐selectin on ECs, where stromal cells and fibroblasts confer signals that contribute to chemotherapy resistance, (ii) ECs, fibroblasts, osteoblast lineage cells, and megakaryocytes secrete excess CXCL12 to the BMME, (iii) ECs secrete miR‐126, which promotes LSC self‐renewal, (iv) leukemia cells secrete exosomes that suppress stromal cell function and osteoblast development, (v) loss of sympathetic nerves is linked to loss of support for Nestin⁺ MSCs, (vi) immune cells such as Tregs and leukemia‐supportive macrophages provide immunosuppressive signals, (vii) leukemic blasts accumulate in the BMME around the HSC niches, where they secrete excess CCL3, TNF, and TPO, (viii) there is an increase in inflammatory signaling, such as IFN‐γ and IL‐1 and, (ix) CCL3 leads to the formation of defective osteoblasts. Abbreviations: BM, bone marrow; BMME, bone marrow microenvironment; CAR/LepR⁺, CXCL12‐abundant reticular cells and leptin receptor+ cells; CCL3, C‐C motif chemokine ligand 3; CXCL12, chemokine (C‐X‐C motif) ligand 12; EC, endothelial cell; GFP, green fluorescent protein; HSC, hematopoietic stem cell; IFN‐γ, interferon γ; IL‐1, interleukin 1; LSC, leukemia stem cell; miR‐126, microRNA‐126; MSC, mesenchymal stromal cell; NG2, Neuron‐Glial Antigen 2; OB, osteoblast; SCF, stem cell factor; TNF, tumor necrosis factor; TPO, thrombopoietin; Treg, T regulatory cell.