Journal
BLOOD
Volume 115, Issue 14, Pages 2891-2900Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-08-236596
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Funding
- UK Medical Research Council
- Leukaemia Research Fund
- Kay Kendall Leukaemia Fund
- NIHR Cambridge Biomedical Research Centre
- Leukemia & Lymphoma Society of America
- Myeloproliferative Disorders Foundation
- Laurette Fugain Association
- Fondation de France
- Ligue Nationale Contre le Cancer
- Canceropole Ile de France
- MRC [G0300497] Funding Source: UKRI
- Cancer Research UK [8961] Funding Source: researchfish
- Medical Research Council [G0300723B, G0300497] Funding Source: researchfish
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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. (Blood. 2010; 115(14): 2891-2900)
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