A Novel JAK2 Fusion in T‐Cell Prolymphocytic Leukemia

Abstract

ABSTRACTT‐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.