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Published on: October 19, 2014
CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression
Erika Tissino1, Federico Pozzo1, Dania Benedetti1
1Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy.
Insights
Bimodal CD49d expression in chronic lymphocytic leukemia (CLL) indicates a more aggressive disease. Analyzing the pattern of CD49d expression, not just the percentage, improves prognostic accuracy for CLL patients.
Area of Science:
- Hematology
- Oncology
- Immunology
Background:
- CD49d is a prognostic biomarker in chronic lymphocytic leukemia (CLL).
- The standard 30% cutoff for CD49d expression doesn't account for expression patterns.
- Bimodal CD49d expression, with both positive and negative subpopulations, is present in approximately 20% of CLL cases.
Purpose of the Study:
- To investigate the clinical significance of bimodal CD49d expression in CLL.
- To determine if CD49d expression patterns impact patient prognosis beyond the established cutoff.
- To analyze the characteristics and behavior of CD49d subpopulations in bimodal CLL.
Main Methods:
- Analysis of 1630 CLL patient samples.
- Flow cytometry to assess CD49d expression patterns (homogeneous vs. bimodal).
- Evaluation of CD49d expression variability in sequential samples and correlation with clinical outcomes in chemoimmunotherapy and ibrutinib treatment settings.
Main Results:
- Identified bimodal CD49d expression in 313/1630 (approx. 20%) CLL cases.
- Bimodal CD49d CLL exhibited higher variability and an increase in CD49d+ cells post-therapy.
- The CD49d+ subpopulation showed increased proliferation and was enriched in bone marrow and specific peripheral blood subsets (CXCR4dim/CD5bright).
- Patients with bimodal CD49d expression had similar clinical behavior to CD49d+ CLL, irrespective of the 30% cutoff.
Conclusions:
- Bimodal CD49d expression is a significant feature in CLL, associated with a more aggressive clinical course.
- The pattern of CD49d expression, in addition to the percentage, is crucial for accurate prognostic assessment in CLL.
- Considering bimodal CD49d expression can enhance the prognostic value of CD49d as a biomarker in CLL management.
Abstract:
CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The cutoff value for the extensively validated 30% of positive CLL cells is able to separate CLL patients into 2 subgroups with different prognoses, but it does not consider the pattern of CD49d expression. In the present study, we analyzed a cohort of 1630 CLL samples and identified the presence of ∼20% of CLL cases (n = 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d+ subpopulation and a CD49d- subpopulation. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49d+ subpopulation over time after therapy. The CD49d+ subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d- cells; and was more highly represented in the bone marrow compared with peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49d+ subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d+ CLL, both in chemoimmunotherapy (n = 1522) and in ibrutinib (n = 158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should also be considered to improve the prognostic impact of this biomarker in CLL.
