Molecular mechanisms associated with leukemic transformation of MPL-mutant myeloproliferative neoplasms.
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.
Beer
Philip A
PA
Cambridge Institute for Medical Research, Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK.
Ortmann
Christina A
CA
Stegelmann
Frank
F
Guglielmelli
Paola
P
Reilly
John T
JT
Larsen
Thomas S
TS
Hasselbalch
Hans C
HC
Vannucchi
Alessandro M
AM
Möller
Peter
P
Döhner
Konstanze
K
Green
Anthony R
AR
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
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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