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

Molecular Cancer

Research

Paula Lam¹  Zhentang Lao²  Trixie Y. H. Lim³  Wan Hwa Ng³  Joey Teo³  Shee Min Goay³  Yuen Rong M. Sim³  Kah Chun Goh³  Gao Bin Chen³  Jia Hao Jackie Teo³  Jiancheng Hu⁴  Kanaga Sabapathy⁴  Jiajun Yap⁴  Jimin Yuan⁵ 

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

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

DOI  :  10.1186/s12943-023-01817-8

 received in 2023-03-14, accepted in 2023-07-04,  发布年份 2023

来源: Springer

【 摘 要 】

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)KI together with Trp53KO or pTENKO 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)KI and Trp53KO or pTENKO 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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

【 图 表 】

13570_2023_282_Article_IEq8.gif

Fig. 5

13690_2023_1151_Article_IEq24.gif

Fig. 3

Fig. 2

Fig. 2

40517_2023_266_Article_IEq58.gif