毛发细胞白血病（HCL）是由BRAF（V600E）突变诱导的B淋巴瘤。然而，将BRAF（V600E）引入B淋巴细胞中未能诱导血液系统恶性肿瘤，这表明BRAF（V600E）需要同时发生其他突变才能推动HCL的发生。为了解决这个问题，我们对人类HCL基因组测序数据进行了调查。结合之前的报告，我们推测肿瘤抑制因子TP53，P27或PTEN限制了BRAF（V600E）在B淋巴细胞中的致癌能力，因此它们的失活有利于BRAF（V600E）驱动的HCL发生。通过使用基因改造的小鼠模型，我们证明了BRAF(V600E)KI和Trp53KO或pTENKO在B淋巴细胞中共同诱导慢性淋巴瘤，并具有类似于人类HCL的病理特征。为了进一步了解HCL发生必需的细胞程序，我们对来自BRAF(V600E)KI和Trp53KO或pTENKO小鼠的白血病细胞的基因表达进行了分析，发现它们具有类似但不同的基因表达特征，类似于M2或M1巨噬细胞。此外，我们还检查了这些白血病细胞中对生发中心反应和记忆B细胞与浆细胞分化所需的转录因子/调控因子的表达特征，发现大多数对这些程序至关重要的转录因子/调控因子被严重抑制，说明为什么毛发细胞停留在活化B细胞和记忆B细胞之间的过渡阶段。总的来说，我们的研究揭示了HCL发生所需的同时发生的突变，揭示了毛发细胞的B细胞起源，研究了该疾病独特病理特征的分子基础，对HCL研究和治疗具有重要意义。 © 2023. BioMed Central Ltd., part of Springer Nature.

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