Abstract
Hematopoietic stem/progenitor cells (HSPC) and leukemia-initiating cells (LIC) require CD44 for homing and survival. As a first step to selectively attack LIC, we explored the engagement of standard versus CD44v6 and CD44v7 variant isoforms (CD44s, CD44v) in HSPC maintenance by antibody blocking, using CD44v7- and CD44v6/ v7-knockout (ko) mice. HSPC matrix protein adhesion is dominated by CD44s. CD44v6 supports migration towards hyaluronan (HA), fibronectin, IL6, OPN, SDF1 and bone marrow stroma cells (BM-StrC), where BM-StrC CD44v7 strongly facilitates HSPC homing. Mitigated adhesion affects quiescence and drug resistance. CD44v6/v7ko HSPC divide more frequently than wild type (wt) HSPC and anti-CD44v6 drives HSPC into proliferation. Apoptosis resistance is supported by HA and BM-StrC and is affected in CD4v6/v7ko HSPC. HA and BM-StrC promote apoptosis resistance via PI3K/Akt pathway activation, which is dampened in CD44v6/v7ko HSPC. Thus, HSPC CD44 contributes to adhesion, migration, quiescence and apoptosis resistance. BM-StrC CD44v7 supports HSPC homing. HA- and BM-StrC-promoted quiescence and apoptosis resistance proceeds via HSPC CD44v6. As HSPC matrix adhesion mostly relies on CD44s, HSPC CD44v6/CD44v7 expression is low and CD44v7 influences the crosstalk with BM-StrC, attacking CD44v6-overexpressing LIC by anti-CD44v6 may not severely affect the HSPC interaction with the osteogenic niche.
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