TY - JOUR
T1 - Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm
AU - Beer, Philip A
AU - Delhommeau, François
AU - LeCouédic, Jean-Pierre
AU - Dawson, Mark A
AU - Chen, Edwin
AU - Bareford, David
AU - Kusec, Rajko
AU - McMullin, Mary Frances
AU - Harrison, Claire N
AU - Vannucchi, Alessandro M
AU - Vainchenker, William
AU - Green, Anthony R
PY - 2010/4/8
Y1 - 2010/4/8
N2 - 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.
AB - 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.
KW - Aged
KW - Blast Crisis
KW - DNA-Binding Proteins
KW - Female
KW - Hematologic Neoplasms
KW - Humans
KW - Janus Kinase 2
KW - Leukemia, Myeloid, Acute
KW - Male
KW - Middle Aged
KW - Mutation
KW - Neoplasms, Second Primary
KW - Primary Myelofibrosis
KW - Proto-Oncogene Proteins
KW - Proto-Oncogene Proteins c-cbl
KW - Tumor Suppressor Protein p53
U2 - 10.1182/blood-2009-08-236596
DO - 10.1182/blood-2009-08-236596
M3 - Article
C2 - 20008300
SN - 0006-4971
VL - 115
SP - 2891
EP - 2900
JO - Blood
JF - Blood
IS - 14
ER -