NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways

Abstract

In chronic lymphocytic leukemia (CLL), stabilizing mutations of NOTCH1, affecting up to 10-15% of cases, have been associated to poor prognosis, disease progression and refractoriness to chemotherapy. NOTCH1 mutations are significantly overrepresented in trisomy 12 CLL, a disease subset frequently expressing CD49d, the α4 chain of the very-late-activation-4 integrin, a well-known key regulator of microenviromental interactions, and negative prognosticator in CLL. In the present study, by analysing a wide cohort of 1180 CLL, we observed a very strong association between the presence of NOTCH1 mutations and the expression of CD49d (P<0.0001), occurring also outside the trisomy 12 CLL subset. Using both the MEC-1 CLL-like cells stably transfected with the NOTCH1 intracellular domain and primary CLL cells bearing a mutated or wild-type NOTCH1 gene configuration, we provide evidence that triggering of the NOTCH1 pathway resulted in a positive CD49d expression regulation, which was driven by a NOTCH1-dependent activation of nuclear factot-κB (NF-κB). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κB pathways resulted in impaired NF-κB nuclear translocation with consequent down-modulation of CD49d expression. Altogether, our data link for the first time NOTCH1 mutations to CD49d expression regulation through the involvement of the NF-κB pathway in CLL.

An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

“…To discuss in details the functional mechanisms behind these prognosticators is behind the scope of the present review. However, some references addressing in details these aspects are the following [108][109][110][111][112][113][114][115].…”

The NOTCH Pathway and Its Mutations in Mature B Cell Malignancies

“…Leukemic cells themselves express NOTCH ligands on the surface, suggesting the existence of autologous signaling ( 57 ). Increased activity of NOTCH1 pathway protects leukemic cells from apoptosis through multiple mechanisms, among which the crosstalk with NF-κB signaling represents a key feature in CLL biology, as it directly regulates expression of anti-apoptotic genes (e.g., c-IAP2 and XIAP) and surface molecules (e.g., CD49d) that facilitate interactions with microenvironment, feeding a pro-leukemic loop ( 58 ) (Figure 4 ). Moreover, NOTCH1 promotes CLL cell growth and active proliferation by upregulating genes related to ribosome biogenesis and protein translation such as NPM1 and ribosomal proteins ( RNPs ) ( 59 ).…”

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

“…In addition, NOTCH1 mutations frequently occur with deletions of the long arm of chromosome 14 ( 56 ), and are inversely correlated with chromosome 11 deletions ( 23 ). NOTCH1 lesions are considerably associated with flow cytometry-based markers of poor prognosis including ZAP-70, CD38, and CD49d ( 26 , 57 – 59 ). Analyses on larger number of patients documented a high frequency of unmutated IGHV genes in both coding and non-coding NOTCH1 -mutated CLL cases ( 60 ).…”

“…A role of NOTCH1 in activating NF-κB has been also demonstrated in recent studies performed in CLL cells with NOTCH1 mutation ( 160 ). In addition, a NOTCH1-dependent activation of NF-κB has been shown to drive the expression of CD49d, a well-known key regulator of microenvironmental interactions and negative prognosticator in CLL ( 59 ). The effect of NOTCH1/NF-κB axis on CD49d expression is stronger in NOTCH1 -mutated CLL cells, but it is not restricted to this CLL subset.…”