Jenny Karoline Jebsen

• Imbery, John Franklin; Wiik, Celina Marie; Heinzelbecker, Julia; Jebsen, Jenny Karoline; Dobbing, Mia K. & Bottini, Nunzio [Show all 12 contributors for this article] (2024). CD38 regulates chronic lymphocytic leukemia proliferation via CD45 phosphatase activity. Molecular Therapy: Oncology. 32(3), p. 1–15. doi: 10.1016/j.omton.2024.200841. Full text in Research Archive Show summary

  Chronic lymphocytic leukemia (CLL) growth is dependent on both B cell receptor (BCR) signaling and signals from microenvironmental T helper (Th) cells. We previously described a mechanism where Th cells enhance BCR signaling and proliferation through CD45 phosphatase activity regulation via galectin-1 and CD43. The CLL negative prognostic indicator CD38 is linked to BCR signaling and proliferation, with its expression induced by Th cells. Here, we explore a link between CD38 and CD45 phosphatase activity regulation using patient-derived material in a Th-CLL cell co-culture model. Results demonstrate CD43 and galectin-1 are co-expressed with CD38, defining proliferative CLL cells with augmented CD45 activity. CD38 enzymatic and receptor inhibition regulated CD43 and galectin-1 expression, CD45 activityhi populations, and CLL proliferation, while leaving Th cells largely unaffected. Mechanistically, CD38- or LGALS1 (galectin-1)-deficient malignant B cell lines further confirmed CD38-mediated regulation of CD45 activity and BCR signaling through CD43 expression and galectin-1 surface binding, while galectin-1 contributed to CD43/CD45 colocalization. Together, this highlights CD38 as an important regulator of CD45 activity via CD43 and galectin-1, in turn acting as a positive modulator of CLL proliferation. Ultimately, the CD38/CD45 molecular hub could be an important therapeutic target in CLL.

• Imbery, John Franklin; Heinzelbecker, Julia; Jebsen, Jenny Karoline; McGowan, Marc Kevin; Myklebust, Camilla Victoria & Bottini, Nunzio [Show all 13 contributors for this article] (2022). T-helper cell regulation of CD45 phosphatase activity by galectin-1 and CD43 governs chronic lymphocytic leukaemia proliferation. British Journal of Haematology. ISSN 0007-1048. 198(3), p. 556–573. doi: 10.1111/bjh.18285. Full text in Research Archive Show summary

  Chronic lymphocytic leukaemia (CLL) is characterised by malignant mature-like B cells. Supportive to CLL cell survival is chronic B-cell receptor (BCR) signalling; however, emerging evidence demonstrates CLL cells proliferate in response to T-helper (Th) cells in a CD40L-dependent manner. We showed provision of Th stimulation via CD40L upregulated CD45 phosphatase activity and BCR signalling in non-malignant B cells. Consequently, we hypothesised Th cell upregulation of CLL cell CD45 activity may be an important regulator of CLL BCR signalling and proliferation. Using patient-derived CLL cells in a culture system with activated autologous Th cells, results revealed increases in both Th and CLL cell CD45 activity, which correlated with enhanced downstream antigen receptor signalling and proliferation. Concomitantly increased was the surface expression of Galectin-1, a CD45 ligand, and CD43, a CLL immunophenotypic marker. Galectin-1/CD43 double expression defined a proliferative CLL cell population with enhanced CD45 activity. Targeting either Galectin-1 or CD43 using silencing, pharmacology, or monoclonal antibody strategies dampened CD45 activity and CLL cell proliferation. These results highlight a mechanism where activated Th cells drive CLL cell BCR signalling and proliferation via Galectin-1 and CD43-mediated regulation of CD45 activity, identifying modulation of CD45 phosphatase activity as a potential therapeutic target in CLL.

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