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Cited by 63Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

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

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Tissino, Erika, Pozzo, Federico, Benedetti, Dania, Caldana, Chiara, Bittolo, Tamara, Rossi, Francesca Maria, Bomben, Riccardo, Nanni, Paola +24 more·2020·Blood
DOI 10.1182/blood.2019003179PMC PMC7228464
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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.

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  • Positive or bimodal CD49d expression portends inferior PFS compared to cases entirely negative for CD49d.

    “Positive or bimodal CD49d expression portends inferior PFS compared to cases entirely negative for CD49d(49, 52).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [52]

    The section on PFS in ibrutinib-treated patients reports shorter PFS for both homogeneous-positive and bimodal CD49d cases than for homogeneous-negative cases. The claim omits that treatment setting, so the source does not establish the PFS comparison for CLL cases generally. (LLM, conf=0.86)

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Authors
Tissino, E., Pozzo, F., Benedetti, D., Caldana, C., Bittolo, T., Rossi, F. M., Bomben, R., Nanni, P., Chivilò, H., Cattarossi, I., Zaina, E., Norris, K., Polesel, J., Gentile, M., Tripepi, G., Moia, R., Santinelli, E., Innocenti, I., Olivieri, J., D’Arena, G., Laurenti, L., Zaja, F., Pozzato, G., Chiarenza, A., Di Raimondo, F., Rossi, D., Pepper, C., Hartmann, T. N., Gaidano, G., Del Poeta, G., Gattei, V., & Zucchetto, A.
Affiliations
  • Centro di Riferimento Oncologico (IT)
  • Cardiff University (GB)
  • Azienda Ospedaliera di Cosenza (IT)
  • Nephrology Center, National Research Institute of Biomedicine and Molecular Immunology, Reggio Calabria, Italy;
  • Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
  • University of Rome Tor Vergata (IT)
  • Agostino Gemelli University Polyclinic (IT)
  • University of Udine (IT)
  • Onco-Haematology Department, Centro di Riferimento Oncologico della Basilicata, IRCCS, Rionero in Vulture, Italy;
  • University of Trieste (IT)
  • University of Catania (IT)
  • Division of Hematology, Ferrarotto Hospital, University of Catania, Catania, Italy;
  • Institute of Oncology Research (CH)
  • Brighton and Sussex Medical School (GB)
  • University of Freiburg (DE)
  • Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
  • Division of Hematology, University of Tor Vergata, Rome, Italy;
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2020-04-09
Volume
135
Issue
15
Pages
1244-1254
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2019003179
PMC
PMC7228464
OpenAlex
W3003932345
Cited by
63
References
1
Citations by year
2026: 4 · 2025: 7 · 2024: 14 · 2023: 7 · 2022: 10 · 2021: 16 · 2020: 5
FWCI
4.92
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
  • RERO DOC (Universität Bern) (submittedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
Funders
  • National Science Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (320030_169670/1)
  • Ministero della Salute (GR-2011-02346826)
  • Associazione Italiana per la Ricerca sul Cancro (IG-21687)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
Keywords
CD49d, chronic lymphocytic leukemia, prognostic factors, disease progression, cell proliferation, bone marrow, ibrutinib, chemoimmunotherapy
MeSH terms
Adenine, Humans, Immunotherapy, Piperidines, Prognosis, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Proportional Hazards Models, Disease Progression, Integrin alpha4, Protein Kinase Inhibitors, Cell Proliferation

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