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of leukemic cells is critically regulated by the transition mechanisms from stem to
progenitor cell, corresponding to metabolic changes, oxygen concentration, cyto-
kine stimulation, or cell contact regulation (Katayama et al. 2006 ). The BM micro-
environment presents an attractive target for novel therapeutic strategies. In
particular, increasing insight into LSC development in their specific BM microenvi-
ronment may ultimately result in novel therapeutic strategies within a framework
for targeting niche cells to attenuate leukemic progression or targeting LSCs with-
out adversely affecting normal stem cell self-renewal.
Reference
Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC et al (2006)
Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor.
Nature 439:599–603
Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D et al (2000) Angiogenesis in
acute and chronic leukemias and myelodysplastic syndromes. Blood 96:2240–2245
Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K et al (2004) Tie2/angiopoietin-1 signal-
ing regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118:149–161
Avigdor A, Goichberg P, Shivtiel S, Dar A, Peled A, Samira S et al (2004) CD44 and hyaluronic
acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone
marrow. Blood 103:2981–2989
Battula VL, Le PM, Sun JC, Nguyen K, Yuan B, Zhou X et al (2017) AML-induced osteogenic
differentiation in mesenchymal stromal cells supports leukemia growth. JCI Insight 2:e90036
Behan JW, Yun JP, Proektor MP, Ehsanipour EA, Arutyunyan A, Moses AS et al (2009) Adipocytes
impair leukemia treatment in mice. Cancer Res 69:7867–7874
Benito J, Shi Y, Szymanska B, Carol H, Boehm I, Lu H et al (2011) Pronounced hypoxia in models
of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104. PLoS One
6:e23108
Bonig H, Papayannopoulou T (2013) Hematopoietic stem cell mobilization: updated conceptual
renditions. Leukemia 27:24–31
Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP, Kunisaki Y et al (2014) Megakaryocytes regu-
late hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 20:1315–1320
Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC et al (2003) Osteoblastic
cells regulate the haematopoietic stem cell niche. Nature 425:841–846
Carracedo A, Cantley LC, Pandolfi PP (2013) Cancer metabolism: fatty acid oxidation in the lime-
light. Nat Rev Cancer 13:227–232
Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al (2004)
Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1.
Nat Med 10:858–864
Cho BS, Zeng Z, Mu H, Wang Z, Konoplev S, McQueen T et al (2015) Antileukemia activity of
the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with
chemotherapy. Blood 126:222–232
Chow A, Lucas D, Hidalgo A, Méndez-Ferrer S, Hashimoto D, Scheiermann C et al (2011) Bone
marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor
cells in the mesenchymal stem cell niche. J Exp Med 208:261–271
Christopher MJ, Liu F, Hilton MJ, Long F, Link DC (2009) Suppression of CXCL12 production by
bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization.
Blood 114:1331–1339
Y. Tabe and M. Konopleva