Hematopathology Service, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Genes Chromosomes Cancer. 2024 Jun;63(6):e23252. doi: 10.1002/gcc.23252.
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell malignancy characterized by marked lymphocytosis, B symptoms, lymphadenopathy, and hepatosplenomegaly. There is no standard treatment approach, and in the absence of an allogeneic transplant, the prognosis remains poor. The disease-defining cytogenetic abnormality in T-PLL is the juxtaposition of the TCL1-family oncogene to the TCR gene enhancer locus primarily due to an inversion of chromosome 14, that is, inv(14). The application of next-generation sequencing technologies led to the discovery of highly recurrent gain-of-function mutations in JAK1/3 and STAT5B in over 70% of T-PLL providing opportunities for therapeutic intervention using small molecule inhibitors. Additional genetic mechanisms that may contribute to the pathogenesis of T-PLL remain unknown. Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T-PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient's disease course over a 25-month post-treatment duration using ruxolitinib and duvelisib.
T 细胞前淋巴细胞白血病（T-PLL）是一种罕见且侵袭性的成熟 T 细胞恶性肿瘤，其特征为明显的淋巴细胞增多、B 症状、淋巴结病和肝脾肿大。目前尚无标准的治疗方法，在没有异体移植的情况下，预后仍然较差。T-PLL 的疾病定义性细胞遗传学异常是 TCL1 家族癌基因与 TCR 基因增强子位点的并置，主要是由于染色体 14 的倒位，即 inv(14)。下一代测序技术的应用导致在超过 70%的 T-PLL 中发现了 JAK1/3 和 STAT5B 的高度复发性获得性功能突变，为使用小分子抑制剂进行治疗干预提供了机会。其他可能有助于 T-PLL 发病机制的遗传机制尚不清楚。在此，我们描述了一种新型基因融合 SMCHD1::JAK2 的鉴定，该融合是由染色体 9 和 18 之间的易位引起的，涉及 SMCHD1 外显子 45 和 JAK2 外显子 14（t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)），这是在携带关键疾病定义性 inv(14)的 T-PLL 患者中以前未描述的遗传事件，导致 TCL1 和 TRA/D 的重排。在本手稿中，我们描述了患者在接受 ruxolitinib 和 duvelisib 治疗后 25 个月的疾病过程中的临床和遗传特征。
