Genetic pathways in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia

Hematology Am Soc Hematol Educ Program. 2007:392-7. doi: 10.1182/asheducation-2007.1.392.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Chromosome Aberrations
  • Epigenesis, Genetic
  • Humans
  • Leukemia, Myeloid, Acute / etiology
  • Leukemia, Myeloid, Acute / genetics*
  • Mutation
  • Myelodysplastic Syndromes / etiology
  • Myelodysplastic Syndromes / genetics*
  • Radiotherapy / adverse effects*

Substances

  • Antineoplastic Agents