ITGA4 negative

CD49d/VLA-4 emerges as a microenvironmental factor that contributes to BTKi resistance in CLL. The prognostic value of CD49d is improved by considering bimodal CD49d expression.

Patients were either untreated (n=2) or treated with chemo-immunotherapy (CIT, n=2) or Ibrutinib post-CIT relapse (n=2) between the first and second sample...Accordingly, CD49d+ CLL cells overexpressed (p=0.0001) the transcription signature of the PF reported by Calissano et al (Mol Med, 2011), as well as the signature of CD49d+ CLL (Zucchetto et al., Cancer Res, 2009). Overall, our WGS approach revealed that CD49d expression is plastic in CD49d bimodal CLL, such plasticity driven by epigenetic events.

There were significant correlations between CD49d and 11q22-, +12 and BIRC3 gene mutation. Patients with bimodal CD49d were more correlated with poor prognosis indexes.

Functionally, EMILIN-1 gC1q domain promotes adhesion of CLL cells through specific interaction with VLA-4, and releases pro-survival signals for CLL cells, as demonstrated by enhanced ERK and AKT phosphorylation and impairment of in-vitro-induced apoptosis. EMILIN-1/VLA-4 interaction can efficiently contribute to the maintenance of the neoplastic clone in CLL.