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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.

Objective: To evaluate the clinical characteristics, treatment response, and outcomes in patients with classical hairy cell leukemia (cHCL) and HCL variant (HCL-V). Methods: This is a retrospective case series study. Between January 2011 and December 2021, clinical data of 30 patients newly with diagnosed HCL at Peking Union Medical College Hospital were analyzed. The main outcome measures include clinical characteristics, treatment efficacy and survival. The Kaplan-Meier method was used for survival analysis. Results: Twenty-one cases of cHCL and 9 cases of HCL-v were included. The median age at diagnosis was 55.5 (range, 30-86) years, with the ratio of male to female 2.75∶1. The main clinical manifestations included fatigue in 11 cases (36.7%), abdominal distension in 7 cases (23.3%), and infection in 4 cases, while 8 cases were asymptomatic. Splenomegaly was reported in 24 cases (80.0%), including 7 (23.3%) with megalosplenia. The white blood cell count, lymphocyte count, and the proportion of peripheral hairy cells in HCL-v group were significantly higher than those in cHCL group, whereas the development of anemia, thrombocytopenia, and monocytopenia in cHCL group was more remarkable than that in HCL-v group (all P<0.05). The BRAF-V600E gene mutation was detected only in cHCL patients (11/14 vs. 0/9, P<0.001). In terms of immunophenotype, the expression of CD25, CD103, CD123 and CD200 in cHCL group (20/20, 20/20, 4/7, 7/17) were all stronger than those in HCL-v group (3/9, 7/9, 0/4, 2/8). Twenty-two patients were treated, of which 13 cases (12 cases of cHCL and 1 case of HCL-v) with cladribine, and 9 cases (4 cHCL and 5 HCL-v) with interferon. Complete remission rate and overall response rate were comparable between cladribine and interferon treatment groups (both P<0.05). The median follow-up time was 31 (range, 1-125) months, and the median overall survival (OS) of the entire group was 125 months. The 5-year OS rate in HCL-v patients represented a trend of inferior (50.0% vs. 95.0%, P=0.207). Conclusions: The clinical features of HCL are unspecific, which includes fatigue, splenomegaly and recurrent infection. The clinical features, immunophenotype, treatment response and prognosis of HCL-v are different from those of cHCL. BRAF-V600E gene mutation is suggested as a key marker for differential diagnosis. Cladribine is recommended as front-line regimen of cHCL patients with satisfactory efficacy and prognosis. Conversely, response and clinical outcome in HCL-v patients still need to be improved.
目的： 分析经典型毛细胞白血病（cHCL）和变异型毛细胞白血病（HCL-v）的临床特征、治疗疗效及生存，并进行对比。 方法： 回顾性病例系列研究。收集2011年1月至2021年12月北京协和医院收治的30例HCL患者的临床资料，分析患者临床特征、治疗疗效及生存情况。生存分析采用Kaplan-Meier法。 结果： 30例患者包括21例cHCL和9例HCL-v。诊断时年龄30~86岁，中位年龄为55.5岁；男女比例为2.75∶1。主要临床表现包括乏力11例（36.7%）、腹胀7例（23.3%）和感染4例，8例无临床症状。诊断时脾大者24例（80.0%），其中巨脾7例（23.3%）。HCL-v患者外周血白细胞计数、淋巴细胞计数及外周血毛细胞比例均显著高于cHCL患者，而cHCL患者出现贫血、血小板减低、单核细胞减低的比例显著高于HCL-v患者，差异均有统计学意义（均P<0.05）。cHCL患者中BRAF-V600E基因突变的阳性率显著高于HCL-v患者（11/14比0/9，P<0.001）。免疫表型方面，cHCL患者CD25、CD103、CD123和CD200的表达率（20/20、20/20、4/7、7/17）均高于HCL-v患者（3/9、7/9、0/4、2/8）。30例患者中22例接受治疗，13例（12例cHCL、1例HCL-v）采用克拉屈滨方案，9例（4例cHCL、5例HCL-v）采用干扰素治疗。克拉曲滨与干扰素治疗的完全缓解率及总反应率差异均无统计学意义（均P>0.05）。中位随访时间为31个月（范围1~125个月）。生存曲线分析显示，总体患者的中位总生存时间为125个月，HCL-v患者相比cHCL患者5年总生存率呈现劣势（50.0%比95.0%），但差异无统计学意义（P=0.207）。 结论： HCL的临床特征缺乏特异性，主要包括乏力、脾大和反复感染。HCL-v临床特征、免疫表型、治疗反应及预后均与cHCL有差异，BRAF-V600E基因突变是区分二者的重要依据。cHCL患者应用克拉曲滨治疗反应率高，预后满意，而HCL-v的疗效及预后仍有待改善。.

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Both characteristics and optimal treatment strategy for hairy cell leukemia-variant (HCL-v) remain elusive due to its rarity. We retrospectively analyzed the clinical features of HCL-v and the efficacy of first-line treatment options in a large Chinese cohort. In this study, we recruited 33 HCL-v patients (23 males and 10 females) with a median age of 59 years (range, 34-79 years). The chief complaints included abdominal mass and relative signs (67%) and abnormal complete blood count (27%). Immunophenotyping showed monoclonal B-cells positive for pan B-cell antigens and CD11c, weakly positive for CD103 and CD200, while negative for CD5, CD10, CD25, CD123, and annexin A1. No BRAF V600E mutation was detected, but TP53 abnormality was recurrent. Treatment choices included interferon-α (IFN-α) in 11 patients, chlorambucil (CLB) in 5 patients, single purine nucleoside analogs (PNA) in 3 patients, PNA plus rituximab (PNA + R) in 9 patients, and others in 3 patients. Four patients who received IFN-α or CLB treatment also underwent splenectomy. Patients who received PNA + R had a higher complete response rate (88% versus 5%, P < 0.001) and longer progression-free survival (PFS, 3-year PFS rate 42% [95% CI 1-84] vs. 16% [95% CI 3-40], P = 0.042) than those who received other regimens. Overall, HCL-v is an indolent lymphoma with unique characteristics. The PNA + R regimen is the preferred choice in the first-line treatment for HCL-v.

BACKGROUND: This case report is presented to improve our understanding of the atypical immunophenotype of hairy cell leukemia.
METHODS: A 58-year-old woman presented to our department with fatigue for >10 days.
METHODS: The patient was diagnosed with an increased proportion of abnormal lymphocytes in peripheral blood and bone marrow smear, positive for CD11c, CD19, CD20, CD22, CD25, CD123, CD200, and Kappa, partial expression of CD23, but no expression of CD103, positive for BRAF V600E mutation.
RESULTS: Cladribine combined with rituximab achieved complete remission of minor residual disease negativity.
CONCLUSIONS: Hairy cell leukemia is rare, and the diagnosis and differential diagnosis should be made by combining the patient\'s medical history, clinical manifestations, immunophenotype, gene detection, and other means. Purine nucleoside analogs are the first-line treatments.

毛细胞白血病（HCL）是一种罕见的、具有独特的形态学和免疫表型的成熟小B细胞淋巴组织增殖性疾病，肿瘤细胞侵犯骨髓和脾脏，骨髓活检是最可靠有效的诊断方法，但常因骨髓纤维化、干抽而不能获得满意的标本。HCL为惰性淋巴瘤，临床进展缓慢，在极短时间内伴发噬血细胞综合征则更是罕见，有待对更多病例进行观察，总结经验，提早预防严重并发症的发生。.

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