Stem Cell Microenvironments and Beyond

27

adhesion, provides growth factors, and promotes immunosuppression (Tabe and
Konopleva 2014 ; Nwajei and Konopleva 2013 ). At the same time, leukemia cells are
constantly adjusting their metabolic state in response to extracellular signaling and/
or nutrient availability by making “decisions” such as quiescence, proliferation or
differentiation in the constantly changing environment. By elucidating the role of
the BM microenvironment in the pathogenesis of hematological tumors, recent
studies have provided insight into the molecular mechanisms involved in stem cell
activation and homing to the BM niche (Fig. 3.1). Long-term quiescence and self-
renewal may be crucial for stress resistance of LSCs, and survival and proliferation

LSC

HSC

LSCLSC

LSC

LSC

LSC

LSC

LSC

LSC

Osteoblast Osteoclast

Tregcell

HSC

HSC HSC

HSC

LSC

macrophage

megakaryocyte

Sympathetic nerve

Arteriole

CAR cell

Endothelial cell

Nestin+ MSC

LepR+ MSC

Osteocyte

activated TGF-β

latent TGF-β

CXCL12

SCF

a b

VCAM1

FN

HA

Fig. 3.1 Key components of the leukemic BM microenvironment and invasion of LSCs. (a)
Components of normal hematopoietic stem cell (HSC) niches consist of multiple cell types includ-
ing osteoblasts, Cxcl12-abundant reticular (CAR) cells, nestin-positive mesenchymal stem cells
(MSCs), LepR-expressing perivascular cells, endothelial cells, immune cells (macrophages and
T-regs) and Schwann cells wrapping sympathetic nerve fibers. (b) Leukemia stem cells (LSCs)
hijack HSC marrow spaces including perivascular and endosteal niches. The BM stromal cells and
osteoblasts produce a complex extracellular matrix (ECM) such as vascular cell adhesion mole-
cule- 1 (VCAM-1) , fibronectin (FN) and hyaluronic acid (HA), which facilitate engraftment and
adhesion of LSCs. Osteoblasts within endosteal niches produce transforming growth factor-β
(TGF-β), which, in turn, promotes leukemia cell dormancy and decreases their chemosensitivity.
CAR cells, nestin-positive MSCs, leptin receptor-positive perivascular cells, and endothelial cells
may play a role in migration of leukemia cells into the BM microenvironment via cytokines, che-
mokines, and adhesion molecules

3 Leukemia Stem Cells Microenvironment