Abstract 19: Braf(v600e) mutation together with loss of trp53 or pten drives the origination of hairy cell leukemia from b-lymphocyte

Abstract

Abstract Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations for driving HCL ontogeny. To resolve this issue, here we surveyed the human HCL genomic sequence data. Together with previous reports, we speculated that tumor suppressor, Trp53, P27, or pTEN restricted the oncogenicity of BRAF(V600E) in B-lymphocytes, whose loss-of-function facilitates the BRAF(V600E)-driven HCL ontogeny. Using genetic mice models, we demonstrated that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induced chronic lymphoma with pathological features of human HCL. To further understand cellular programs essential for HCL ontogeny, we next profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that these leukemic cells had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, which illustrates why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations for HCL ontogeny, revealed the B cell origination of hairy cells as well as molecular basis that underlies unique pathological features of this disease, and hence has important implications in both HCL research and clinic treatment. Citation Format: Jiajun Yap, Jimin Yuan, Bin Gao Chen, Wan Hwa Ng, Yuen Rong M. Sim, Kah Chun Goh, Jiancheng Hu. Braf(v600e) mutation together with loss of trp53 or pten drives the origination of hairy cell leukemia from b-lymphocyte [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 19.