LSC survival signaling in the CP CML BMM. The schematic diagram of the BMM shows key (but not exhaustive) pathway components that mediate signaling between the LSC (light red) and other BMM cell types. HSC is shown in blue. OB, osteoblast cells (tan). Ligands involved in various signaling pathways are shown as small, colored spheres. IL-1/IL-1RAP regulates NFKβ signaling in LSCs and can be blocked using a monoclonal antibody to IL-1RAP.135 MPL, the thrombopoietin (TPO) receptor, regulates JAK/STAT signaling and CML patients with high MPL expression on their LSCs have reduced sensitivity to BCR-ABL1 kinase inhibition with TKI, but a higher sensitivity to JAK inhibitors.139 Leukemic progenitor expansion is driven by exposure of LSC, overexpressing BMPR1B, to BMP2 and BMP4.127 The CML BMM is also thought to overexpress the NOTCH ligand JAGGED-1, implicating NOTCH signaling in LSC quiescence.138 LSCs stimulate the production of placental growth factor (PIGF) by BM stromal cells that work in a positive feedback loop to increase angiogenesis of the BM and promote CML cell proliferation through FLT1 (VEGFR1) signaling.140 Stimulation of BM osteoblasts with parathyroid hormone (PTH) resulted in bone remodelling and production of TGF-β1, eradicated LSCs by stimulating TGF-β signaling142 (the opposite effect to other reports of TGF-β signaling in LSCs58,122 ). Similarly, others have shown that expansion of the osteoblast layer of the CML BMM can contribute to creating a hostile environment for HSCs; these effects are mediated by TPO, CCL3, and direct cell–cell interactions that alter TGF-β, NOTCH, and pro-inflammatory signaling in the remodelled osteoblasts.148 Other abbreviations are as described in the text. Other features are as described in Figures 2 and 3.
