Adhesion Molecules in Normal Hematopoiesis and Leukemia - Adhesion Molecules - page 361

Leukemia, the modulation of adhesion molecules by dif erentiating agents such
as the all- trans retinoic acid (ATRA) and arsenic trioxide constitute the molecular
basis of dif erentiation syndrome, a life-threatening complication of the treatment.
In the present chapter, we review some key aspects of the role of adhesion molecules
in normal and malignant hematopoiesis.
ADHESION MOLECULES IN NORMAL AND LEUKEMIC
STEM CELLS NICHE
Hematopoietic stem cells require a specii c microenvironment in order to self-renew
or commit to dif erentiate. h e term 'niche' designates this microenvironment,
which is composed of stromal cells (macrophages, endothelial cells, adipocytes,
reticular cells and T cells) and of extracellular matrix molecules. h ere are
myriad interactions between hematopoietic stem cells and the niche, some of
them dependent on the adhesion molecules. From the anatomical point of view,
hematopoietic stem cells reside along the endosteal surface of trabecular bone in
close proximity to the bone-forming osteoblasts (forming the osteoblastic niche)
and the endothelial cells that line blood vessels (vascular niche). Two adhesion
molecules exert a pivotal role in the osteoblastic niche function: N-cadherin
and β-catenin, which are asymmetrically localized at the interface between
hematopoietic stem cells and the osteoblastic niche (Zhang et al . 2003) and are
thought to facilitate the anchoring of stem cells. However, Haug et al . (2008)
have demonstrated that bone marrow cells expressing high levels of N-cadherin
were unable to reconstitute hematopoietic lineages in irradiated recipient mice
in contrast to those expressing low levels of N-cadherin and expressing genes
known to prime hematopoietic stem cells to mobilize. In fact, N-cadherin
expression at low levels was more frequent in hematopoietic stem cells mobilized
from bone marrow to spleen. h erefore, it has been proposed that N-cadherin is
required to maintain hematopoietic stem cell adhesion to the niche, to regulate
quiescence, to regulate β-catenin signaling, and to maintain hematopoietic stem
cells in an undif erentiated state. h is concept has been recently challenged by the
demonstration that the conditional deletion of N-cadherin from hematopoietic
stem cells and other hematopoietic cells in adult mice had no detectable ef ect on
hematopoietic stem cell maintenance or hematopoiesis (Kiel et al . 2009).
Hematopoietic stem cells also express the integrins α4β1 (also named very late
antigen 4, VLA-4) and α5β1 (VLA-5), which are involved in the adhesion to bone
marrow stromal cells through i bronectin. Moreover, α4β1-mediated adhesion
promoted proliferation and prevented apoptosis of hematopoietic stem cells
(Wang et al . 1998) and the hematopoietic stem cells from β1-integrin-dei cient
failed to colonize the spleen and bone marrow (Potocnik et al . 2000). Nevertheless,
Brakebusch et al . (2002), using a conditional model in which the deletion of β-1
integrin was restricted to the hematopoetic cells, demonstrated that the mutants