Sequential Development of [JAK2.sup.V617F] Mutation and BCR-ABL1 Fusion in Individual Patients With Myeloproliferative Neoplasms: A Linear Clonal Evolution or Parallel Clonal Competition?

* Context.--Concomitant BCR-ABL1 and [JAK2.sup.V617F] in myeloproliferative neoplasms (MPNs) is rare, and its pathogenesis and clinical significance are unclear. Objective.--To investigate the clonal relationship between the 2 genomic alterations, as well as the clinicopathologic impact. Design.--Retrospective analysis of MPNs with sequential development of BCR-ABL1 and [JAK2.sup.V617F]. Results.--Of 6 cases, 5 had [JAK2.sup.V617F]-positive MPN diagnosed before acquiring BCR-ABL1 years later, and 1 had [BCR-ABL1.sup.+] chronic myeloid leukemia before [JAK2.sup.V617F]-positive myelofibrosis completely replaced the BCR-[ABL1.sup.+] clone 1 year after tyrosine kinase inhibitor therapy. Among the former group, treatment for the initial MPN involved hydroxyurea, ruxolitinib, and/or supportive care, and the latency to the development of [JAK2.sup.V617F] ranged from 4 to 13 years (median of 9 years). Four cases showed retention of [JAK2.sup.V617F], whereas BCR-ABL1 emerged as the major clone, including 2 cases that exhibited parallel increases in [JAK2.sup.V617F] and BCR-ABL1 burdens, with both genomic markers exceeding 50%. Three patients received stem cell transplants and demonstrated sustained engraftment, with the genomic markers below detectable levels. Conclusions.--Most MPNs with concomitant [JAK2.sup.V617F] and BCR-ABL1 are actually composite MPNs with a 'second hit' residing on a different clone. Rare cases demonstrate a subclone harboring a 'double-hit' in a background of a [JAK2.sup.V617F]-positive stem line clone. The probability of a 'double-hit' with a BCR-[ABL1.sup.+] stem line clone is probably reduced by effective tyrosine kinase inhibitor treatment. The treatment often involves combined kinase inhibitors and/or hydroxyurea, but the outcome is unpredictable; hematopoietic stem cell transplantation may be the ultimate therapeutic option for this complicated disease.
BCR-ABL1 fusion and [JAK2.sup.V617F] mutation are 2 genomic aberrations defining different subtypes of myeloproliferative neoplasms (MPNs). The current World Health Organization classification scheme separates MPNs by the presence or absence [...]