Understanding Hairy Cell Leukemia in the Context of Mature B‑ Cell Neoplasms: Tumor Microenvironment and Extracellular Vesicle contribution to disease pathogenesis

Vincenzo Ingangi¹Dominga Amoroso¹Eugenia Passaro²Vincenzo Di Vaia¹Filippo Maltoni³Ghazal Narimanfar⁴Michele Minopoli¹Rita Rosa²Mariateresa Ametrano¹Elena Di Gennaro²Alessandro Broccoli^3,4Pier Luigi Zinzani^3,4Lucia Catani^3,4*Chiara Ciardiello^1*

• ¹Preclinical Models of Tumor Progression Unit, G. Pascale National Cancer Institute Foundation (IRCCS), Naples, Italy
• ²Experimental Pharmacology Unit, G. Pascale National Cancer Institute Foundation (IRCCS), Naples, Italy
• ³IRCCS Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology “L. e A. Seràgnoli”, Bologna, Italy
• ⁴Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

Mature B-cell neoplasms constitute a biologically and clinically heterogeneous group of hematologic malignancies, defined by the clonal proliferation and accumulation of monotypic mature B lymphocytes, which may involve the peripheral blood, bone marrow (BM), lymphoid tissues, or present in extranodal sites. While the pathogenesis of common subtypes such as chronic lymphocytic leukemia, multiple myeloma, Hodgkin Lymphoma and Diffuse Large B-cell Lymphoma has been extensively studied, that of rare entities like Hairy Cell Leukemia (HCL) remains poorly understood. HCL is a distinct B cell neoplasm marked by BM infiltration of atypical “hairy” cells, pancytopenia, BM fibrosis, and the BRAF V600E mutation, a defining molecular hallmark of the classic form of the disease. Analogous to solid tumors, growing evidence shows that the tumor microenvironment (TME) is a pivotal contributor to the initiation and progression of these malignancies. However, in rare mature B cell neoplasms, understanding how tumor cells interact with their microenvironment—through immune invasion, stromal crosstalk, and tissue remodelling—remains challenging, partly due to the scarcity of patient samples and limited availability of preclinical models. Extracellular vesicles (EVs) have emerged as central mediators of intercellular communication in both solid and hematological malignancies. EVs modulate tumor–microenvironment interactions, influencing disease progression, immune modulation, and treatment response by delivering bioactive cargo within the tumor milieu. This review places HCL within the broader spectrum of mature B cell neoplasms, highlighting current knowledge on the crosstalk between malignant B cells and their TME. Particular attention is given to EVs, which play immuno regulatory roles by interacting with immune and non immune components of the TME, including stromal cells. We examine EV driven mechanisms relevant to HCL, offering a unifying framework for integrating complex interactions that remain under investigated in rare disease settings. Building on this synthesis, we propose that insights from well characterized lymphoproliferative disorders may provide a foundation for studying related but poorly understood conditions such as HCL. Furthermore, given the scarcity of biological samples and reliable preclinical models for rare hematological malignancies, we highlight the value of coordinated European biobanks, which provide access to well annotated clinical samples essential for interdisciplinary research and advanced experimental modelling.