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. 2020 Sep 29;12(10):2806. doi: 10.3390/cancers12102806

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© 2020 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Interaction of haematopoietic stem cells (HSC) and FLT3 ITD-positive blast cells with the haematopoietic bone marrow niche. (a) Under physiological conditions, HSC are recruited and immobilised via the chemokine CXCL12, produced by bone marrow stromal cells in the perivascular niche. On HSC CXCL12 binds to and activates the G-protein coupled chemokine receptor CXCR4. HSC give rise to more restricted progenitor cells that fuel differentiated peripheral blood cells. (b) FLT3 ITD⁺ leukaemic blast cells shape the bone marrow haematopoietic niche. Through activation of the cytoplasmic serine/threonine kinase Pim1, FLT3 ITD enhances CXCR4 signalling and mediates leukaemic blast recruitment to the perivascular niche. Through the induction of tumour necrosis factor (TNF)-expression in endothelial cells, leukaemic blast cells drive TNF-mediated decay of stroma cells and in consequence, impaired normal haematopoiesis. (c) The perivascular niche, in particular stromal cells contribute to tyrosine kinase inhibitor (TKI)-resistance through (I) secretion of cytokines and growth factors that enable bypassing of inhibited FLT3 ITD and (II) CYP3A4-mediated catabolism of TKI in stromal cells.