Selective pressure as an essential force in molecular evolution of myeloid leukemic clones

A view from the window of Fanconi anemia

M. W. Lensch, R. K. Rathbun, Susan Olson, G. R. Jones, G. C. Bagby

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Specific chromosomal deletions are commonly found in bone marrow cells of children with Fanconi anemia (FA) whose disease has evolved to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Identical deletions are found in adults with MDS/AML with a history of exposure to alkylating agents (secondary MDS/AML). While deleted chromosomal regions likely harbor genes encoding proteins with tumor suppressor (TS) function, such genes have not been identified and the environmental forces by which these mutant clones are selected remain unclear. A consistent signaling abnormality in cells bearing mutations of the Fanconi anemia complementation group C (FA-C) gene (FANCC) has revealed a potential selective force. Hematopoietic progenitor cells from patients and mice with FANCC mutations are hypersensitive to the inhibitory effects of IFNγ and TNFα. Consequently, clonal outgrowths in FA likely result from strong selective pressure for stem and/or progenitor cells resistant to these inhibitory cytokines. Additional mutations that inactivate signaling pathways for these inhibitors would create a cell with a profound proliferative advantage over its apoptosis-prone counterparts. Here, we present preliminary evidence supporting a selection-based model of leukemic evolution and argue that MDS in FA patients is a de facto model of secondary MDS in non-FA adults.

Original languageEnglish (US)
Pages (from-to)1784-1789
Number of pages6
JournalLeukemia
Volume13
Issue number11
StatePublished - 1999

Fingerprint

Fanconi Anemia
Molecular Evolution
Myelodysplastic Syndromes
Clone Cells
Acute Myeloid Leukemia
Mutation
Stem Cells
Alkylating Agents
Hematopoietic Stem Cells
Bone Marrow Cells
Genes
Anemia
Apoptosis
Cytokines
Neoplasms
Proteins

Keywords

  • Acute myeloid leukemia
  • Clonal evolution
  • Cytogenetics
  • Fanconi anemia
  • Molecular evolution
  • Myelodysplasia

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Selective pressure as an essential force in molecular evolution of myeloid leukemic clones : A view from the window of Fanconi anemia. / Lensch, M. W.; Rathbun, R. K.; Olson, Susan; Jones, G. R.; Bagby, G. C.

In: Leukemia, Vol. 13, No. 11, 1999, p. 1784-1789.

Research output: Contribution to journalArticle

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