25molecule- 1, to support vascular adhesion (Stucki et al. 2001 ). It has been further
demonstrated that INTEGRIN β 3 knockdown impairs homing, downregulates LSC
transcriptional programs, and induces differentiation via the intracellular kinase
Syk without affecting normal HSCs (Miller et al. 2013 ).
3.2.5 Hypoxia/HIF-1α Signaling and BM Vasculature
Overexpression of the hypoxia-regulated component hypoxia-inducible factor 1α
(HIF-1α) has been shown in clusters of leukemia cells in BM specimens (Wellmann
et al. 2004 ). Hypoxia affects LSC cycling, quiescence, metabolism and chemother-
apy resistance, and HIF-1α could serve as a putative prognostic marker for high-risk
leukemia and potential therapeutic target (Griessinger et al. 2014 ). HIF-1α-induced
quiescence supports chemoresistance of AML cells (Griessinger et al. 2014 ; Drolle
et al. 2015 ). The suppression of reactive oxygen species (ROS) and endoplasmic
reticulum stress are the main proposed mechanisms of HIF-1α-induced anti-
apoptosis in LSCs (Zhang et al. 2012 ). It has also been demonstrated that HIF-1α
upregulates CXCL12 gene expression in endothelial cells (Ceradini et al. 2004 ) and
CXCR4 expression in AML cells (Fiegl et al. 2009 ), which increases migration and
homing of circulating CXCR4-positive AML cells into ischemic tissue. Hypoxia
could favor LSC niche metabolism, too (Korn and Méndez-Ferrer 2017 ). However,
some studies have demonstrated that deleting HIF-1α induces AML and MPN pro-
gression (Velasco-Hernandez et al. 2014 , 2015 ). These controversial results reflect
the complexity of BM environmental control of leukemia cells. One of the key func-
tions of hypoxia and HIF-1α is upregulation of growth factor vascular endothelial
growth factor (VEGF) and stimulation of angiogenesis. Myeloid leukemia includ-
ing AML, MPN, and MDS is correlated with increased BM angiogenesis (Hussong
et al. 2000 ; Aguayo et al. 2000 ; Lundberg et al. 2000 ; Medinger et al. 2009 ; Pruneri
et al. 1999 ; Ferrara et al. 2003 ), and disorganized BM vascularization is a common
niche change in myeloid malignancies. The microvasculature) is an active compo-
nent of the BM microenvironment, supplying appropriate oxygen and nutrients.
VEGF secreted by leukemic cells activates receptors on both leukemic and endothe-
lial cells and plays a vital role in the growth of leukemia cells (Ferrara et al. 2003 ).
The direct HIF-1α inhibitor PX-478 decreases hypoxia-mediated VEGF expression
in tumor xenografts, resulting in antitumor activity (Koh et al. 2008 ). Angiogenesis
is stimulated in the LSC microenvironment, despite the lower oxygen tension in the
BM than in arterial blood (Benito et al. 2011 ). However, it remains difficult to define
the BM stem cell niche as severely hypoxic (Bonig and Papayannopoulou 2013 ).
A quantitative imaging study demonstrated that HSCs in the endosteal BM niche
closely interact with BM microvessels and yet highly express HIF1α, indicating that
the hypoxic profile is at least, in part, through a cell-intrinsic mechanism rather than
a lack of blood supply (Nombela-Arrieta et al. 2013 ). In fact, cytokines), hormones,
and genetic modifications can stimulate HIF-1α signaling (Kuschel et al. 2012 ).
3 Leukemia Stem Cells Microenvironment