title: Molecular mechanisms associated with leukemic transformation of MPL-mutant myeloproliferative neoplasms.
abstract: Somatic activating mutations in MPL, the thrombopoietin receptor, occur in the myeloproliferative neoplasms, although virtually nothing is known about their role in evolution to acute myeloid leukemia. In this study, the MPL T487A mutation, identified in de novo acute myeloid leukemia, was not detected in 172 patients with a myeloproliferative neoplasm. In patients with a prior MPL W515L-mutant myeloproliferative neoplasm, leukemic transformation was accompanied by MPL-mutant leukemic blasts, was seen in the absence of prior cytoreductive therapy and often involved loss of wild-type MPL by mitotic recombination. Moreover, clonal analysis of progenitor colonies at the time of leukemic transformation revealed the presence of multiple genetically distinct but phylogenetically-related clones bearing different TP53 mutations, implying a mutator-phenotype and indicating that leukemic transformation may be preceded by the parallel expansion of diverse hematopoietic clones.
authors.affiliation: Cambridge Institute for Medical Research, Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: Christina A
authors.initials: CA
authors.lastname: Ortmann
authors.forename: Frank
authors.initials: F
authors.lastname: Stegelmann
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: John T
authors.initials: JT
authors.lastname: Reilly
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Larsen
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hasselbalch
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000208:Acute Disease; D019943:Amino Acid Substitution; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D018450:Disease Progression; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D008957:Models, Genetic; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D053628:Receptors, Thrombopoietin; D016159:Tumor Suppressor Protein p53; C082218:MPL protein, human; D049308:Dioxygenases; C541081:TET2 protein, human
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