title: 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.
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Cambridge, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: François
authors.initials: F
authors.lastname: Delhommeau
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: LeCouédic
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dawson
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Bareford
authors.forename: Rajko
authors.initials: R
authors.lastname: Kusec
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: McMullin
authors.forename: Claire N
authors.initials: CN
authors.lastname: Harrison
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000368:Aged; D001752:Blast Crisis / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D005260:Female; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D049308:Dioxygenases; C541081:TET2 protein, human; D050721:Proto-Oncogene Proteins c-cbl; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C067419:CBL protein, human