TY - JOUR
T1 - CD49d promotes disease progression in chronic lymphocytic leukemia: New insights from CD49d bimodal expression
AU - Tissino, Erika
AU - Pozzo, Federico
AU - Benedetti, Dania
AU - Caldana, Chiara
AU - Bittolo, Tamara
AU - Rossi, Francesca Maria
AU - Rossi, Federica Maria
AU - Bomben, Riccardo
AU - Nanni, Paola
AU - Chivilò, Hillarj
AU - Cattarossi, Ilaria
AU - Zaina, Eva
AU - Zaina, Elisabetta
AU - Norris, Kevin
AU - Polesel, Jerry
AU - Gentile, Massimo
AU - Gentile, Marino
AU - Tripepi, Giovanni
AU - Moia, Riccardo
AU - Santinelli, Enrico
AU - Innocenti, Idanna
AU - Olivieri, Jacopo
AU - D'Arena, Giovanni
AU - Laurenti, Luca
AU - Zaja, Francesco
AU - Pozzato, Gabriele
AU - Chiarenza, Annalisa
AU - Di Raimondo, Francesco
AU - Rossi, Davide
AU - Rossi, Dario
AU - Pepper, Chris
AU - Hartmann, Tanja Nicole
AU - Gaidano, Gianluca
AU - Del Poeta, Giovanni
AU - Gattei, Valter
AU - Zucchetto, Antonella
PY - 2020
Y1 - 2020
N2 - 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 5 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d1 subpopulation and a CD49d2 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 CD49d1 subpopulation over time after therapy. The CD49d1 subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d2 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 CD49d1 subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d1 CLL, both in chemoimmunotherapy (n 5 1522) and in ibrutinib (n 5 158) 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.
AB - 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 5 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d1 subpopulation and a CD49d2 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 CD49d1 subpopulation over time after therapy. The CD49d1 subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d2 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 CD49d1 subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d1 CLL, both in chemoimmunotherapy (n 5 1522) and in ibrutinib (n 5 158) 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.
KW - Cell Proliferation
KW - Disease Progression
KW - Humans
KW - Immunotherapy
KW - Integrin alpha4
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Prognosis
KW - Proportional Hazards Models
KW - Protein Kinase Inhibitors
KW - Pyrazoles
KW - Pyrimidines
KW - Cell Proliferation
KW - Disease Progression
KW - Humans
KW - Immunotherapy
KW - Integrin alpha4
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Prognosis
KW - Proportional Hazards Models
KW - Protein Kinase Inhibitors
KW - Pyrazoles
KW - Pyrimidines
UR - http://hdl.handle.net/10807/184012
U2 - 10.1182/BLOOD.2019003179
DO - 10.1182/BLOOD.2019003179
M3 - Article
SN - 0006-4971
VL - 135
SP - 1244
EP - 1254
JO - Blood
JF - Blood
ER -