engleski

Two routes to leukemic transformation following a JAK2 mutation-positive myeloproliferative neoplasm

Acute myeloid leukemia (AML) may follow a JAK2-positive myeloproliferative neoplasm (MPN), although the mechanisms of disease evolution, often involving loss of mutant JAK2, remain obscure. We studied 16 patients with JAK2-mutant (7/16) or JAK2 wild-type (9/16) AML following a JAK2-mutant MPN. Primary myelofibrosis or myelofibrotic transformation preceded all 7 JAK2-mutant but only one of 9 JAK2 wild-type AMLs (p=0.001), implying that JAK2-mutant AML is preceded by mutation(s) that give rise to a 'myelofibrosis' phenotype. Loss of the JAK2 mutation by mitotic recombination, gene conversion or deletion was excluded in all wild-type AMLs. A search for additional mutations identified alterations of RUNX1, WT1, TP53, CBL, NRAS and TET2, without significant differences between JAK2-mutant and wild-type leukemias. In 4 patients, mutations in TP53, CBL or TET2 were present in JAK2 wild-type leukemic blasts but absent from the JAK2-mutant MPN. By contrast in a chronic phase patient, clones harboring mutations in JAK2 or MPL represented the progeny of a shared TET2-mutant ancestral clone. These results indicate that different pathogenetic mechanisms underlie transformation to JAK2 wild-type and JAK2-mutant AML, demonstrate that TET2 mutations may be present in a clone distinct from that harboring a JAK2 mutation and emphasize the clonal heterogeneity of the MPNs.

MPN; transformation; leukemia; JAK2

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