Figure 1.

Effect of inducible deficiency of Twist1 in the bone marrow niche. (A) Normal bone marrow (BM) niche. The normal BM niche constists of multiple cell types, including non-hematopoietic endothelial cells (EC), CXCL12-expressing adventitial cells (CAR cells), Leptin-receptor-positive cells (LepR+ cells), Nestin – green fluorescent protein high-expressing cells [Nestin-GFP(high) cells], myelinated fibers (surrounded by Schwann cells) and non-myelinated sympathetic fibers; mesenchymal stem cells (MSC); osteoblasts; and adipocytes; and hematopoietic cells that include regulatory T cells (Treg), macrophages (Mac) and osteoclasts (OC). The mechanisms used by these cells to control HSC activity include expression of short-acting hormones, cytokines and chemokines, leptin, stem cell factor (SCF); angiopoietin; thrombopoietin (TPO); C-X-C motif chemokine 12 (CXCL12); transforming growth factor-beta (TGFβ); neurotransmitters (norepinephrine and neuropeptide Y) and purine nucleotides (ATP and adenosine); extracellular proteins [osteopontin (OPN), fibronectin, and others] and direct cell-to-cell, contact-dependent interactions (e.g. CXCL12-CXCR4; integrin-VCAM1) and transfer of organelles and secondary messengers. (B) The effect of a Twist1-deficient BM niche on HSC. Twist1 deficiency in BM niche causes EC expansion and angiogenesis, depletion of MSC, increased OPN production and decreased intramarrow levels of CXCL12, VCAM1 and SCF production while OPN production increases, which impairs HSC retention in the BM niche and promotes their mobilization to the periphery. (C) The effect of a Twist1-deficient BM niche on leukemic stem cells (LSC). The Twist1-deficient BM niche promotes acute myelogenous leukemia (AML) after transformation by the MLL-AF9 oncogene. The mechanism involves upregulated Notch signaling through upregulation of the production of local Jagged-2 (expressed by EC, osteoblasts and MSC) and the membrane expression of Notch receptors on LSC.