Co-occurrence of JAK2-V617 F mutation and BCR::ABL1 translocation in chronic myeloproliferative neoplasms: a potentially confounding genetic combination

Abstract

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome–positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2-positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient’s treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented.

Chronic myeloproliferative neoplasms with concomitant CALR mutation and BCR::ABL1 translocation: diagnostic and therapeutic implications of a rare hybrid disease

“…BCR::ABL1 rearrangement, at the basis of CML development, and JAK2 mutations were initially considered mutually exclusive genetic alterations. However, since JAK2 first discovery in 2005, an increasing number of patients with concomitant BCR::ABL1 rearrangement and JAK2 mutations have been reported, and in a recent comprehensive review of the literature, we identified 87 cases carrying both genetic abnormalities ( Zanelli et al, 2024 ).…”

“…In our recent review analyzing BCR::ABL1/JAK2 V617F double-positive cases, the majority of patients fell into the group of JAK2 -mutated MPN preceding CML (49.42%) ( Zanelli et al, 2024 ).…”

“…The CALR -mutated MPNs received different treatments (HU, anagrelide, IFN, and ruxolitinib) often as sequential therapies; however, data on the outcome are often incomplete and scarce; therefore, further studies are essential to establish the optimal management. In BCR::ABL1/JAK2 double-positive cases, interesting results have been reported with allo-HSCT, which may be a superior therapeutic option ( Zanelli et al, 2024 ). This therapeutic strategy has been adopted in only two cases with concomitant BCR::ABL1 and CALR , and outcome data were available just in one case, which obtained complete remission of both CML and Ph-negative MPN with undetectable genetic markers ( Boddu et al, 2018 ).…”