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3.1 Introduction
The dynamic interactions between leukemic cells and bone marrow (BM) cells in
the leukemia BM microenvironment regulate leukemia stem cell (LSC) properties
including localization, self-renewal, differentiation, and proliferation (Tabe and
Konopleva 2014 ). Despite the significant progress that has been achieved in
chemotherapy- based and targeted treatments of several leukemia subsets, relapse
remains common after an initial response (Dores et al. 2012 ; Sant et al. 2010 ), indi-
cating the persistence of chemoresistant LSCs in the BM. Recent research of normal
and leukemia BM microenvironments has revealed several key components of spe-
cific niches that provide a sanctuary where subpopulations of leukemia cells evade
chemotherapy-induced death and acquire a drug-resistant phenotype, as well as the
molecular pathways critical for microenvironment/leukemia interactions.
Although the biology of LSCs shares many similarities with that of normal
hematopoietic stem cells (HSCs), LSCs are able to outcompete HSCs and hijack
BM niches. Increasing evidence indicates that these niches fuel the growth of leuke-
mia cells and contribute to therapeutic resistance and the metastatic potential of
leukemia cells by shielding LSCs (Hanahan and Coussens 2012 ; Tabe et al. 2017 ).
Not only “microenvironment-induced oncogenesis,” but also a “malignancy-
induced microenvironment” have been proposed (Shiozawa and Taichman 2010 ).
BM niches are part of a complex of BM cells including bone-lining cells (osteo-
blasts and osteoclasts), mesenchymal stem cells (MSCs), sinusoidal endothelium
and perivascular stromal cells, nonmyelinating Schwann cells and immune cells,
which play distinct roles in the regulation of hematopoiesis (Ding et al. 2012 ;
Kunisaki et al. 2013 ) Chemokine receptors (Rombouts et al. 2004 ; Zeng et al. 2009 ;
Tabe et al. 2013 ; Nervi et al. 2009 ), adhesion molecules (Jin et al. 2006 ; Williams
et al. 2013 ; Redondo-Muñoz et al. 2008 ; Jacamo et al. 2014 ), the sympathetic ner-
vous system (Katayama et al. 2006 ), hypoxia-related proteins (Wellmann et al.
2004 ; Suda et al. 2011 ), and genetic and epigenetic abnormalities of leukemia-
associated stroma cells have been proposed as key emerging therapeutic targets
(Walkley et al. 2007a). In this chapter, the key components and regulation of BM
niches in leukemic BM is described. In addition, metabolic changes in LSCs, which
are currently a subject of intense investigation, will also be discussed to understand
LSC survival.
3.2 Leukemic Microenvironment
3.2.1 Components of Microenvironmental Niches
Endosteal and vascular niches are anatomically closely related to distinct vascular
structures, arterioles, and sinusoids, which work in concert (Ding et al. 2012 ;
Kunisaki et al. 2013 ; Calvi et al. 2003 ; Kiel and Morrison 2008 ; Adams et al. 2006 ;
Y. Tabe and M. Konopleva