BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes

Yap，Jiajun1,2; Yuan，Jimin1,2,3,4; Ng，Wan Hwa1; Chen，Gao Bin1; Sim，Yuen Rong M.1; Goh，Kah Chun1; Teo，Joey1; Lim，Trixie Y.H.1; Goay，Shee Min1; Teo，Jia Hao Jackie1; Lao，Zhentang5; Lam，Paula2,6,7; Sabapathy，Kanaga1,2; Hu，Jiancheng1,2

2023-12-01

10.1186/s12943-023-01817-8

Molecular Cancer   Impact Factor & Quartile

1476-4598

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 to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E) together with Trp53 or pTEN in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E) and Trp53 or pTEN mice, and found that they 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, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment.

B cell biology B cell lymphoma BRAF(V600E) Hairy cell leukemia RAS/RAF/MEK/ERK signaling Tumor suppressor

SCI

English

Others

Biochemistry & Molecular Biology ; Oncology

Biochemistry & Molecular Biology ; Oncology

WOS:001043339700001

BMC

2-s2.0-85166597491

Scopus

1.Division of Cellular and Molecular Research,National Cancer Centre Singapore,Singapore,30 Hospital Boulevard,168583,Singapore
2.Cancer and Stem Cell Program,Duke-NUS Medical School,Singapore,8 College Road,169857,Singapore
3.Department of Urology,The Second Clinical Medical College,The First Affiliated Hospital,Shenzhen People’s Hospital,Jinan University,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China
4.Geriatric Department,The Second Clinical Medical College,The First Affiliated Hospital,Shenzhen People’s Hospital,Jinan University,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China
5.Department of Hematology,Singapore General Hospital,Singapore,Blk7 Outram Road,169608,Singapore
6.Department of Physiology,National University of Singapore,Singapore,2 Medical Drive,117597,Singapore
7.Cellvec Pte. Ltd,Singapore,100 Pasir Panjang Road,118518,Singapore

Yap，Jiajun,Yuan，Jimin,Ng，Wan Hwa,et al. BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes[J]. Molecular Cancer,2023,22(1).

Yap，Jiajun.,Yuan，Jimin.,Ng，Wan Hwa.,Chen，Gao Bin.,Sim，Yuen Rong M..,...&Hu，Jiancheng.(2023).BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes.Molecular Cancer,22(1).

Yap，Jiajun,et al."BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes".Molecular Cancer 22.1(2023).