23may reflect disruption of normal hematopoietic progenitor cell niches and creation
of leukemia niches by leukemic cells (Colmone et al. 2008 ).
3.2.3 CXCR4–CXCL12 Interactions and LSC Migration
to the BM
Interactions between LSCs and BM niches are recognized as the major cause of
leukemia relapse. Leukemia cells highjack normal BM vascular niches dependent
upon CXCL12 and E-selectin (Colmone et al. 2008 ). The chemokine CXCL12,
produced by CAR cells, Nestin+ MSCs, and osteoblasts, is a key factor mediating
homing and engraftment of LSCs into the BM niche. Levels of the CXCL12 recep-
tor CXCR4 are significantly elevated in leukemia cells (Raaijmakers 2014 ), and the
association between CXCR4 expression with the poor outcome of patients with
leukemia has been reported (Rombouts et al. 2004 ). Of note, chemotherapy for
patients with AML and imatinib treatment in patients with CML upregulates
CXCR4 expression, which results in increased CXCL12/CXCR4 signaling and
lodging into BM niches, fostering chemoresistance (Zeng et al. 2009 ; Sison et al.
2013 ; Tabe et al. 2012 ). Inhibiting CXCL12–CXCR4 interactions results in abolish-
ment of CXCL12-induced chemotaxis, inactivation of prosurvival signaling path-
ways including phosphorylation of p44/42 mitogen-activated protein kinase and
signal tranducer and activator of transcription 3 (STAT3), and decreases in BM
stromal protective effects on chemotherapy-induced apoptosis in CLL and AML
cells (Zeng et al. 2009 ; Zeng et al. 2006 ; Cho et al. 2015 ). Recruitment of CXCR4
and its downstream mediator Lyn into lipid rafts in CML cells contributes to ima-
tinib resistance (Tabe et al. 2012 ). BM stromal cell-derived TGF-β1 is also known
as a mediator of resistance during cytarabine treatment of AML (Tabe et al. 2013 ).
Combined treatment with the CXCR4 inhibitor plerixafor, the TGFβ-neutralizing
antibody 1D11, and cytarabine decreases the leukemia burden and prolongs survival
in a leukemia mouse model, demonstrating that TGFβ and CXCL12 play a role in
AML chemoresistance (Tabe et al. 2013 ). Overall, CXCL12–CXCR4 interactions
in the BM microenvironment contribute to the chemoresistance of leukemic cells,
and disruption of these interactions by CXCR4 inhibitors represents a rational strat-
egy for blocking LSC homing to the BM niche and/or sensitizing AML cells to
chemotherapy or kinase inhibitors. Clinical trials exploring this concept are under-
way (Uy et al. 2012 ); NCT02652871.
3.2.4 Adhesion of LSCs to the BM Niche
Adhesion to the stromal niche is crucial for LSCs because it directly supports self-
renewal and protects cells from damage by chemotherapy. The transmembrane gly-
coprotein CD44 of LSCs, existing as a standard isoform (CD44s) and a range of
3 Leukemia Stem Cells Microenvironment