CD49d prevails over the novel recurrent mutations as independent prognosticator of overall survival in chronic lymphocytic leukemia.
CD49d, the alpha-chain of the integrin heterodimer α4β1, was identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p chromosome involving TP53. In addition to TP53, the clinical relevance of NOTCH1, SF3B1 and BIRC3 gene mutations has been recently emphasized. By analyzing a cohort of 778 unselected CLL patients, we assessed the clinical relevance of CD49d as an OS predictor in subgroups defined by mutation/deletion of the TP53, NOTCH1, SF3B1 and BIRC3 genes. In this context, CD49d emerged as an independent predictor of OS in multivariate Cox analysis (Hazard ratio =1.88, P<0.0001). Consistently, high CD49d expression identified CLL subsets with inferior OS in the context of each category of a previously reported hierarchical risk stratification model. Moreover, by evaluating the relative importance of biological prognosticators by random survival forests, CD49d was selected among the top-ranked OS predictor (variable importance =0.0410), along with IGHV mutational status and TP53 abnormalities. These results confirmed CD49d as an independent negative OS prognosticator in CLL also in comprehensive models comprising the novel recurrent mutations. In this context, TP53 disruption and NOTCH1 mutations retained prognostic relevance, in keeping with their roles in CLL cell immuno-chemoresistance.
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
M
M
Dal Bo
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
P
P
Bulian
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
R
R
Bomben
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
A
A
Zucchetto
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
F M
FM
Rossi
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
F
F
Pozzo
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
E
E
Tissino
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
D
D
Benedetti
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
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T
Bittolo
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
P
P
Nanni
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
I
I
Cattarossi
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
E
E
Zaina
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
H
H
Chivilò
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
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M
Degan
Clinica Ematologica, Centro Trapianti e Terapie Cellulari 'Carlo Melzi' DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy.
F
F
Zaja
Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy.
G
G
Pozzato
Division of Hematology, Ferrarotto Hospital, Catania, Italy.
A
A
Chiarenza
Division of Hematology, Ferrarotto Hospital, Catania, Italy.
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F
Di Raimondo
Division of Hematology, S. Eugenio Hospital, University of Tor Vergata, Rome, Italy.
M I
MI
Del Principe
Division of Hematology, S. Eugenio Hospital, University of Tor Vergata, Rome, Italy.
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G
Del Poeta
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
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D
Rossi
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
G
G
Gaidano
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
V
V
Gattei
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D039441:Integrin alpha4 / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000401:mortality*; D008875:Middle Aged; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D011379:Prognosis; D000072260:RNA Splicing Factors / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D011947:Receptors, Antigen, B-Cell; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D039441:Integrin alpha4; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases