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Despite recent advances in the treatment of hematologic malignancies, relapse still remains a consistent issue. One of the primary contributors to relapse is the bone marrow microenvironment providing a sanctuary to malignant cells. These cells interact with bone marrow components such as osteoblasts and stromal cells, extracellular matrix proteins, and soluble factors. These interactions, mediated by the cell surface proteins like cellular adhesion molecules (CAMs), induce intracellular signaling that leads to the development of bone marrow microenvironment-induced chemoprotection (BMC). Although extensive study has gone into these CAMs, including the development of targeted therapies, very little focus in hematologic malignancies has been put on a family of cell surface proteins that are just as important for mediating bone marrow interactions: the transmembrane 4 superfamily (tetraspanins; TSPANs). TSPANs are known to be important mediators of microenvironmental interactions and metastasis based on numerous studies in solid tumors. Recently, evidence of their possible role in hematologic malignancies, specifically in the regulation of cellular adhesion, bone marrow homing, intracellular signaling, and stem cell dynamics in malignant hematologic cells has come to light. Many of these effects are facilitated by associations with CAMs and other receptors on the cell surface in TSPAN-enriched microdomains. This could suggest that TSPANs play an important role in mediating BMC in hematologic malignancies and could be used as therapeutic targets. In this review, we discuss TSPAN structure and function in hematologic cells, their interactions with different cell surface and signaling proteins, and possible ways to target/inhibit their effects., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In an effort to identify acute myeloid leukemia (AML)-restricted targets for therapeutic development in AML, we analyzed the transcriptomes of 2051 children and young adults with AML and compared the expression profile with normal marrow specimens. This analysis identified a large cohort of AML-restricted genes with high expression in AML, but low to no expression in normal hematopoiesis. Mesothelin (MSLN), a known therapeutic target in solid tumors, was shown to be highly overexpressed in 36% of the AML cohort (range, 5-1077.6 transcripts per million [TPM]) and virtually absent in normal marrow (range, 0.1-10.7 TPM). We verified MSLN transcript expression by quantitative reverse transcription polymerase chain reaction, confirmed cell surface protein expression on leukemic blasts by multidimensional flow cytometry, and demonstrated that MSLN expression was associated with promoter hypomethylation. MSLN was highly expressed in patients with KMT2A rearrangements (P < .001), core-binding factor fusions [inv(16)/t(16;16), P < .001; t(8;21), P < .001], and extramedullary disease (P = .001). We also demonstrated the presence of soluble MSLN in diagnostic serum specimens using an MSLN-directed enzyme-linked immunosorbent assay. In vitro and in vivo preclinical efficacy of the MSLN-directed antibody-drug conjugates (ADCs) anetumab ravtansine and anti-MSLN-DGN462 were evaluated in MSLN+ leukemia cell lines in vitro and in vivo, as well as in patient-derived xenografts. Treatment with ADCs resulted in potent target-dependent cytotoxicity in MSLN+ AML. In this study, we demonstrate that MSLN is expressed in a significant proportion of patients with AML and holds significant promise as a diagnostic and therapeutic target in AML, and that MSLN-directed therapeutic strategies, including ADCs, warrant further clinical investigation., (© 2021 by The American Society of Hematology.)

Relapse remains a major obstacle to achieving 100% overall survival rate in pediatric hematologic malignancies like acute lymphoblastic leukemia (ALL). Relapse often results from the development of chemoresistance. One of the mechanisms of chemoresistance involves ALL cell interactions with the bone marrow (BM) microenvironment, providing a sanctuary. This phenomenon is known as BM microenvironment-induced chemoprotection. Members of the transmembrane 4 superfamily (tetraspanins; TSPANs) are known to mediate microenvironmental interactions and have been extensively studied in solid tumors. Although the TSPAN family member CD81 is a minimal residual disease marker, its biological role in ALL is not well characterized. We show for the first time that CD81 knockout induces chemosensitivity, reduces cellular adhesion, and disrupts in vivo BM homing and engraftment in B-ALL. This chemosensitization is mediated through control of Bruton tyrosine kinase signaling and induction of p53-mediated cell death. We then show how CD81-related signaling can be disrupted by treatment with the epigenetic drug combination of DNA hypomethylating agent azacitidine (aza) and histone deacetylase inhibitor panobinostat (pano), which we previously used to sensitize ALL cells to chemotherapy under conditions that promote BM microenvironment-induced chemoprotection. Aza/pano-mediated modulation of CD81 surface expression is involved in decreasing BM load by promoting ALL cell mobilization from BM to peripheral blood and increasing response to chemotherapy in disseminated patient-derived xenograft models. This study identifies the novel role of CD81 in BM microenvironment-induced chemoprotection and delineates the mechanism by which aza/pano successfully sensitizes ALL cells via modulation of CD81., (© 2020 by The American Society of Hematology.)