Identification of RNPC3 as a novel JAK2 fusion partner gene in B‐acute lymphoblastic leukemia refractory to combination therapy including ruxolitinib

Abstract

Background Hematopoietic neoplasms with chromosomal translocations involving JAK2 are rare, and most of them show myeloproliferative neoplasm‐associated features, followed by B‐acute lymphoblastic leukemia (B‐ALL). De novo B‐ALL cases with JAK2 rearrangements are suggested to be appropriately considered as BCR‐ABL1‐like B‐ALL, but its partners varied. Methods Fluorescence in situ hybridization (FISH), RNA sequencing (RNA‐Seq), whole‐genome sequencing, and reverse transcription polymerase chain reaction (RT‐PCR) were performed to identify the pathogenic fusion gene in a 29‐year‐old woman with relapsed B‐ALL and rare t(1;9)(p13;p22) translocation. Results We identified RNPC3 as a new JAK2 fusion partner in the patient. She was treated with a combination of chemotherapy and targeted drug ruxolitinib and chimeric antigen receptor T‐cell therapy, but failed to achieve complete remission. She had no chance to undergo allogeneic hematopoietic stem cell transplantation and died of disease progression 7 months after the initial diagnosis. Her clinical course demonstrated that this novel RNPC3‐JAK2 fusion might portend an unfavorable prognosis. Conclusion This finding adds to the expanding compendium of JAK2 fusions found in B‐ALL and suggests the potential need for a diagnostic FISH analysis as well as RNA‐Seq in the appropriate clinical setting.

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

“…Four of the 10 patients received combined treatments with ruxolitinib. The patient with GOLGA5-JAK2 achieved a CR with high dose ruxolitinib (40 mg/m 2 , bid) ( 18 ), while neither the patient with RNPC3-JAK2 ( 19 ) nor the current one with STRBP-JAK2 responded to ruxolitinib. In our patient, ruxolitinib was administered at the standard dosage used for treatment of myeloproliferative diseases (20 mg bid), and whether she would benefit from an increased dose remains unknown.…”

Efficacy of ruxolitinib in B‐lymphoblastic leukaemia with the PCM1–JAK2 fusion gene

“…Two patients with a myeloid neoplasm and PCM1–JAK2 fusion gene showed a rapid initial response but relapsed after 18 and 24 months respectively 9 . A recent publication by the same group including additional patients, confirmed that responses to ruxolitinib may be transient 10 …”

“…Combining ruxolitinib and chemotherapy could be an alternative for patients who are unresponsive to first‐line therapy or are not eligible for allogeneic stem cell transplantation (SCT). Furthermore, ruxolitinib could be beneficial as a bridging therapy prior to allogeneic SCT, as has already been proposed in myeloid neoplasms 10,11 …”

“…JAK2 inhibitors have been previously used in B‐ALL carrying other JAK2 rearrangements, as an adjuvant to classical chemotherapy 10–12 . In a 10‐year‐old boy diagnosed with a high‐risk B‐ALL and the GOLGA5–JAK2 fusion gene, combined ruxolitinib and post‐induction chemotherapy led to complete morphological and molecular remission, but persistent residual disease by flow cytometry 11 .…”

“…In a 29‐year‐old female with a B‐ALL and RNCP3–JAK2 fusion gene, ruxolitinib combined with chimaeric antigen receptor (CAR) T‐cell therapy and chemotherapy, was started after an early relapse on classic induction therapy. After three months there was still no morphological improvement and the patient eventually died after giving up treatment 10 . A third report describes a 17‐year‐old female with a B‐ALL and an F694L mutation in JAK2 who presented with an early post‐induction relapse.…”