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

Abstract:

: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 of 16) or JAK2 wild-type (9 of 16) AML after a JAK2-mutant MPN. Primary myelofibrosis or myelofibrotic transformation preceded all 7 JAK2-mutant but only 1 of 9 JAK2 wild-type AMLs (P = .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, show that TET2 mutations may be present in a clone distinct from that harboring a JAK2 mutation, and emphasize the clonal heterogeneity of the MPNs.

journal_name

Blood

journal_title

Blood

authors

Beer PA,Delhommeau F,LeCouédic JP,Dawson MA,Chen E,Bareford D,Kusec R,McMullin MF,Harrison CN,Vannucchi AM,Vainchenker W,Green AR

doi

10.1182/blood-2009-08-236596

subject

Has Abstract

pub_date

2010-04-08 00:00:00

pages

2891-900

issue

14

eissn

0006-4971

issn

1528-0020

pii

blood-2009-08-236596

journal_volume

115

pub_type

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