Genetic pathways in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia.
In therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), at least eight alternative genetic pathways have been defined based on characteristic recurrent chromosome abnormalities. Patients presenting as t-MDS and patients presenting as overt t-AML cluster differently in these pathways. The cytogenetic pattern depends on the type of leukemogenic therapy received: alkylating agents, topoisomerase II inhibitors, or radiotherapy. Three types of gene mutations are observed in MDS and AML: (1) Activating mutations of genes in the tyrosine kinase-RAS/BRAF signal transduction pathway, leading to increased cell proliferation (Class I mutations); (2) Inactivating mutations of genes encoding hematopoietic transcription factors, resulting in disturbed cell differentiation (Class II mutations); and (3) Inactivating mutations of the tumor suppressor gene p53. At least 14 different genes have been identified as mutated in t-MDS and t-AML, clustering differently and characteristically in the eight genetic pathways. Class I and Class II mutations are significantly associated, indicating their cooperation in leukemogenesis The chromosome aberrations and gene mutations detected in the therapy-related and in the de novo subsets of MDS and AML are identical, although the frequencies with which they are observed may differ. Hence, therapy-related and de novo MDS and AML are identical diseases and should be subclassified and treated similarly.
Pedersen-Bjergaard
Jens
J
Chromosome Laboratory, Section 4052, Rigshospitalet, Blegdamsvej 9, DK 2100, Copenhagen, Denmark. chromjpb@rh.dk
Andersen
Morten T
MT
Andersen
Mette K
MK
D000970:Antineoplastic Agents / Q000009:adverse effects*; D002869:Chromosome Aberrations; D044127:Epigenesis, Genetic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects*
D000970:Antineoplastic Agents