CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression.

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.

• Authors: Erika Tissino, Federico Pozzo, Dania Benedetti, Chiara Caldana, Tamara Bittolo, Francesca Maria Rossi, Riccardo Bomben, Paola Nanni, Hillarj Chivilò, Ilaria Cattarossi, Eva Zaina, Kevin Norris, Jerry Polesel, Massimo Gentile, Giovanni Tripepi, Riccardo Moia, Enrico Santinelli, Idanna Innocenti, Jacopo Olivieri, Giovanni D'Arena, Luca Laurenti, Francesco Zaja, Gabriele Pozzato, Annalisa Chiarenza, Francesco Di Raimondo, Davide Rossi, Chris Pepper, Tanja Nicole Hartmann, Gianluca Gaidano, Giovanni Del Poeta, Valter Gattei, Antonella Zucchetto
• Journal: Blood (Blood) Vol. 135 Issue 15 Pg. 1244-1254 (04 09 2020) ISSN: 1528-0020 [Electronic] United States
• PMID: 32006000 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• Piperidines
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Integrin alpha4
• ibrutinib
• Adenine

Topics

• Adenine (analogs & derivatives)
• Cell Proliferation (drug effects)
• Disease Progression
• Humans
• Immunotherapy
• Integrin alpha4 (analysis)
• Leukemia, Lymphocytic, Chronic, B-Cell (diagnosis, pathology, therapy)
• Piperidines
• Prognosis
• Proportional Hazards Models
• Protein Kinase Inhibitors (therapeutic use)
• Pyrazoles (therapeutic use)
• Pyrimidines (therapeutic use)