毛细胞白血病和毛细胞白血病变异型患者免疫球蛋白重链可变区基因分子特征分析

  目的  本研究归纳毛细胞白血病（hairy cell leukemia，HCL）和毛细胞白血病变异型（hairy cell leukemia-variant，HCL-v）患者免疫球蛋白重链可变区（immunoglobulin heavy chain variable region，IGHV）基因分子特征，并探讨其与临床特征及预后的相关性。  方法  回顾性分析2004年12月至2020年1月在中国医学科学院血液病医院完善IGHV检测的29例HCL患者和15例HCL-v患者临床和生存资料。  结果   44例患者共检测出23种重排片段，VH4和VH4-34分别是两种疾病最常见的V区基因家族和重排片段。HCL和HCL-v患者中IGHV为突变状态的比例分别为72.4%和66.7%，发生VH4-34重排（VH4-34 rearrangement，VH4-34+）的患者IGHV突变率更低（P<0.001）。在HCL中，使用VH1基因家族患者脾大发生率更低（P=0.041）；而VH4-34+或IGHV未突变状态（IGHV-unmutated，IGHV-UM）的患者具有更高的乳酸脱氢酶（VH4-34+ P=0.049，IGHV-UM P=0.022）和β2微球蛋白（VH4-34+ P=0.039，IGHV-UM P=0.036）水平，且VH4-34+患者BRAF V600E突变率更低（20% vs. 85%，P=0.012）。单因素预后分析显示，VH4-34+是HCL患者无进展生存（progression-free survival，PFS）（P=0.001）和总生存（P=0.004）的不良预后因素，IGHV-UM则为HCL-v患者PFS（P=0.038）的危险因素。  结论  HCL和HCL-v患者对VH4基因家族及VH4-34存在偏向性使用，VH4-34+和IGHV-UM间存在明显共现性。在HCL中，VH4-34+与高肿瘤负荷及更差生存相关，而IGHV-UM是HCL-v患者PFS的危险因素。 

Molecular characteristics of immunoglobulin heavy chain variable region genes in patients with hairy cell leukemia and hairy cell leukemia-variant

Objective: To identify the molecular characteristics of immunoglobulin heavy chain variable region (IGHV) genes in patients with hairy cell leukemia (HCL) and hairy cell leukemia-variant (HCL-v) and explore their correlation with clinical presentation and prognosis. Methods: A retrospective study was conducted to analyze the clinical and survival data of patients with HCL and HCL-v who completed IGHV testing in Institute of Hematology & Blood Diseases Hospital between December 2004 and January 2020. Results: In this study, 44 patients (29 with HCL and 15 with HCL-v) were included. A total of 23 rearrangements were sequenced, and VH4 and VH4-34 were the most frequently used gene family and fragment, respectively. The proportions of patients with an IGHV mutated status for HCL and HCL-v were 72.4% and 66.7%, respectively. Patients with VH4-34 rearrangement (VH4-34+) had a lower IGHV mutation rate (P<0.001) than those with other rearrangements. Patients with HCL with VH1 rearrangement had a lower incidence of splenomegaly (P=0.041), while patients with VH4-34+ or unmutated IGHV (IGHV-UM) had higher lactate dehydrogenase (VH4-34+ P=0.049, IGHV-UM P=0.022) and β₂ microglobulin (VH4-34+ P=0.039, IGHV-UM P=0.035) levels. It was noted that the BRAF V600E mutation was uncommon in patients with HCL with VH4-34+ (20% vs. 85%, P=0.012). Further univariate analysis showed that VH4-34+ was a negative prognostic factor for progression-free survival (PFS)(P=0.001) and overall survival (P=0.004) in HCL, and IGHV-UM was an adverse prognostic factor for PFS (P=0.038) in HCL-v. Conclusions: HCL and HCL-v showed preferential uses of the VH4 gene family and VH4-34 fragment. Moreover, there was obvious co-occurrence of VH4-34+ and IGHV-UM. VH4-34+ was associated with a high tumor load and poor survival in HCL, while IGHV-UM was a risk factor against PFS in HCL-v.