Abstract
Philadelphia chromosome-like B-lymphoblastic leukemia (Ph-like ALL) describes a group of genetically heterogeneous, Ph-negative entities with high relapse rates and poor prognoses. A Janus-kinase-2 (JAK2) rearrangement has been reported in approximately 7% of Ph-like ALL patients whose therapeutic responses to JAK inhibitors have been studied in clinical trials. Here, we report a novel STRBP-JAK2 fusion gene in a 21-year-old woman with Ph-like ALL. Although a normal karyotype was observed, a hitherto unreported JAK2 rearrangement was detected cytogenetically. STRBP-JAK2 fusion was identified by RNA sequencing and validated by Sanger sequencing. The Ph-like ALL proved refractory to traditional induction chemotherapy combined with ruxolitinib. The patient consented to infusion of autologous chimeric antigen receptor (CAR) T cells against both CD19 and CD22, which induced morphologic remission. Haplo-identical stem cell transplantation was then performed; however, she suffered relapse at just one month after transplantation. The patient subsequently received donor lymphocyte infusion after which she achieved and maintained a minimal residual disease negative remission. However, she succumbed to grade IV graft-versus-host disease 7 months post-transplant. In conclusion, this report describes a novel STRBP-JAK2 gene fusion in a Ph-like ALL patient with a very aggressive disease course, which proved resistant to chemotherapy combined with ruxolitinib but sensitive to immunotherapy. Our study suggests that CAR T-cell therapy may be a viable option for this type of leukemia.
Highlights
Philadelphia chromosome-like B-lymphoblastic leukemia (Phlike ALL) is characterized by a gene expression profile resembling Ph-positive ALL (Ph+ ALL) despite an absence of BCR-ABL1 rearrangement
JAK2 is located on chromosome 9p24, and encodes a nonreceptor tyrosine kinase that participates in the activation of the JAK-STAT pathway and plays a central role in regulating cell proliferation, differentiation, survival, and apoptosis during hematopoiesis [6]
JAK2 contains an N-terminal FERM domain that is required for erythropoietin receptor association, a central Src homology 2 (SH2) domain that binds to STAT transcription factors, a pseudokinase domain (JH2) and a Cterminal tyrosine kinase domain (JH1) (Figure 2D)
Summary
Philadelphia chromosome-like B-lymphoblastic leukemia (Phlike ALL) is characterized by a gene expression profile resembling Ph-positive ALL (Ph+ ALL) despite an absence of BCR-ABL1 rearrangement. Activation of the JAK-STAT pathway occurs in approximately 64% of Ph-like ALL patients, including 42% with CRLF2 rearrangements and 22% with non-CRLF2 rearrangements, both of which are therapeutically targeted by JAK inhibitors [1]. Chromosomal translocations, inversions, and deletions generating JAK2 fusion genes and JAK-STAT activation occur in 7% of Ph-like ALL patients [2]. 23 different partner genes are reportedly rearranged with JAK2 in Ph-like ALL, including ATF71P, BCR, EBF1, ETV6, OFD1, PAX5, and ZBTB46 [3]. Most reports of these fusion genes have only presented genetic profiles at the expense of clinical findings. There are only limited data detailing the efficacy of JAK inhibitors and immunotherapy in patients with different JAK2 rearrangements
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