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(Jin et al. 2006 ). Treg cells provide a relative immune sanctuary for stem cells on the
endosteal surface and participate in creating the BM niche and supporting stem cell
function (Kfoury et al. 2014 ; Fujisaki et al. 2011 ). Macrophages promote retention
of HSCs by regulating CXCL12 production in the BM (Chow et al. 2011 ).
Megakaryocytes, localized with a subset of HSCs, promote stem cell quiescence
through the production of CXCL4 (Bruns et al. 2014 ) and TGF-β (Zhao et al. 2014 ).
3.2.2 Modulation of the LSC Niche
The behavior of LSC is modulated by interactions and signals received within their
BM microenvironment (Calvi et al. 2003 ; Kiel and Morrison 2008 ; Arai et al. 2004 ;
Nilsson et al. 2005 ). Although LSCs share certain self-renewal and differentiation
features with HSCs, they differ in their dysregulated activation of key pathways
controlling proliferation, survival and invasion (Lane 2012 ). One study reported that
BM niche components contribute to determining the leukemia phenotype by pro-
viding the necessary cytokines and cell contact-mediated signals to LSCs
(Raaijmakers et al. 2010 ). LSCs, in turn, contribute to deregulation of the BM niche
by their dominant proliferation-promoting signals, and MSCs participate in this
process. MSCs in the BM constitute a heterogeneous population (Raaijmakers
2014 ), and heterotypic signaling from diseased “reprogrammed” MSCs may affect
other cells in the BM. For example, MSCs are required to drive the initiation and
progression of myelodysplastic syndrome (MDS), which is characterized by BM
failure and predisposition for evolution into AML. Transcriptional profiling revealed
the aberrant gene expression implicated in intercellular crosstalk, osteo/adipogene-
sis, inflammation, and fibrosis in MDS MSCs (Raaijmakers 2014 ). Deficiency of
phosphatase and tensin homolog, a tumor suppressor and antagonist of the phos-
phoinositide 3-kinase pathway in hematopoietic cells and BM cells results in myelo-
proliferation that progresses to overt leukemia/lymphoma (Yilmaz et al. 2006 ).
These findings support the concept of niche-induced oncogenesis; primary stromal
dysfunction can result in secondary neoplastic disease. As a frontier study, Walkley
et al. reported that dysfunction of the retinoblastoma protein, a central regulator of
the cell cycle and a tumor suppressor, or of retinoic acid receptor-γ in the BM
microenvironment contributes to the development of preleukemic myeloprolifera-
tive disease from originally nonmutated hematopoietic cells (Walkley et al. 2007a,
b). In another study, conditional knockout of DICER1, a gene that regulates
microRNA processing, in osteoblastic precursors resulted in BM failure and a pre-
disposition for leukemia. Deleting DICER1 causes reduced expression of SBDS, a
gene mutated in Schwachman–Bodian–Diamond syndrome. Deletion of SBDS in
mouse osteoprogenitors induces myelodysplasia and the development of AML
(Raaijmakers et al. 2010 ). On the other hand, LSCs themselves create a “foster
home,” inducing reversible changes in BM stromal cell function or composition that
result in survival of leukemic cells (Dührsen and Hossfeld 1996 ). Suppression of
normal hematopoiesis in patients with leukemia and a relatively low tumor burden
Y. Tabe and M. Konopleva