Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders

Abstract

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a lymphoproliferative disorder in patients treated with MTX. The mechanism of pathogenesis is still elusive, but it is thought to be a complex interplay of factors, such as underlying autoimmune disease activity, MTX use, Epstein-Barr virus infection, and aging. The NOTCH genes encode receptors for a signaling pathway that regulates various fundamental cellular processes, such as proliferation and differentiation during embryonic development. Mutations of NOTCH1 have been reported in B-cell tumors, including chronic lymphocytic leukemia/lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). Recently, it has also been reported that NOTCH1 mutations are found in post-transplant lymphoproliferative disorders, and in CD20-positive cells in angioimmunoblastic T-cell lymphoma, which might be associated with lymphomagenesis in immunodeficiency. In this study, to investigate the association of NOTCH1 in the pathogenesis of MTX-LPD, we evaluated protein expression of Notch1 in nuclei immunohistochemically in MTX-LPD cases [histologically DLBCL-type (n = 24) and classical Hodgkin lymphoma (CHL)-type (n = 24)] and de novo lymphoma cases [DLBCL (n = 19) and CHL (n = 15)]. The results showed that among MTX-LPD cases, the expression of Notch1 protein was significantly higher in the DLBCL type than in the CHL type ( P < 0.001). In addition, among DLBCL morphology cases, expression of Notch1 tended to be higher in MTX-LPD than in the de novo group; however this difference was not significant ( P = 0.0605). The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary.

Targeting Notch signaling pathways with natural bioactive compounds: a promising approach against cancer

“…Activation of Notch signaling has been implicated in pathogenesis of various hematologic tumors including leukemias ( Hubmann et al, 2020 ; Zhang et al, 2022 ; Skelin et al, 2024 ) and lymphomas ( Alderuccio and Lossos, 2022 ). For example, in lymphopoiesis, the Notch1 activation may be involved in the correct differentiation of T and B cells ( Okatani et al, 2024 ). In chronic lymphocytic leukaemia, Notch1 may represent a potential druggable target ( Pozzo et al, 2022 ), suggesting that phytochemicals, such as EGCG and curcumin, may be beneficial in the treatment of chronic lymphocytic leukemia (CLL).…”