Identification of STRBP as a Novel JAK2 Fusion Partner Gene in a Young Adult With Philadelphia Chromosome-Like B-Lymphoblastic Leukemia

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.

Partial Anchored Capture and Long-Read Sequencing (PACLseq) Enable a Stand-alone Diagnostic Method for Ph-like Acute Lymphoblastic Leukemia

“…The copyright holder for this preprint this version posted August 21, 2023. ; https://doi.org/10.1101/2023.08. 19.23294152 doi: medRxiv preprint gene depth. In Group C, the clinical fusion detection was indeterminate, precluding the establishment of a gold standard.…”

“…Each of these genes may have different breakpoints and partner genes, leading to distinct fusion transcripts. Currently, a total of 83 fusions have been reported [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], and it is anticipated that more fusions will be discovered in the future with the advancement of next-generation sequencing (NGS) technologies. The detection of fusions serves not only as a diagnostic tool but also as a foundation for subsequent targeted therapy decisions.…”

“…The copyright holder for this preprint this version posted August 21, 2023. ; https://doi.org/10.1101/2023.08. 19.23294152 doi: medRxiv preprint thereby enhancing the detection of new fusion transcripts. However, both of these concepts lack thorough validation [33,34].…”

Sustained remission after ruxolitinib and chimeric antigen receptor T‐cell therapy bridged to a second allogeneic hematopoietic stem cell transplantation for relapsed Philadelphia chromosome‐like B‐cell precursor acute lymphoblastic leukemia with novel NPHP3‐JAK2 fusion

“…Nevertheless, identification of this fusion has critical clinical significance as it can be a molecular marker for disease classification, targeted therapy, and sensitive minimal residual disease monitoring. The clinical effects varied in cases with different JAK2 fusions, especially in BCP ALL, 7 and JAK2 inhibitors are now mainly used as adjuvant therapy. CD19 CAR-T therapy provided another powerful tool for refractory BCP ALL and showed a better outcome when bridged to a consolidative allo-HSCT.…”

“…Deletion of the JH2 domain may enhance the tyrosine kinase activity of JAK2 and increase the phosphorylation of a variety of intracellular signaling molecules. 7 Moreover, the coiled-coil domain of NPHP3 is reserved in the NPHP3-JAK2 fusion protein, which may conduce to the dimerization or oligomerization of NPHP3-JAK2 chimera and consequently result in constitutive activation of JAK2, deregulated cell proliferation, and resistance to apoptosis. 8 The reported Ph-like BCP ALL cases with JAK2 rearrangements often presented with unfavorable outcomes.…”