Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia

M. William Lensch, Marc Tischkowitz, Tracy A. Christianson, Carol A. Reifsteck, S. Ashley Speckhart, Petra M. Jakobs, Michael E. O'Dwyer, Susan Olson, Michelle M. Le Beau, Shirley V. Hodgson, Chistopher G. Mathew, Richard A. Larson, Grover C. Bagby

Research output: Contribution to journalArticle

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Abstract

Myelodysplastic and leukemic stem cell clones that evolve in children and adults with Fanconi anemia universally bear complex cytogenetic abnormalities. The abnormalities are generally recurring deletions or chromosomal loss and involve precisely the same chromosomes with the same frequency as has been described in marrow cells from patients with secondary acute leukemia induced by alkylating agents. Reasoning that acquired Fanconi anemia protein dysfunction might contribute to cytogenetic instability in secondary acute myelogenous leukemia (AML) cells, we analyzed leukemic cells bearing characteristic complex cytogenetic defects obtained from a 68 year-old man whose lymphoblasts showed no evidence of Fanconi anemia. Unlike the lymphoblasts, this myeloid leukemia cell line (UoC-M1) was hypersensitive to mitomycin-C (MMC) and diepoxybutane (DEB) and exhibited a marked decrease in nuclear FANCA, FANCG, and FANCD2-L. Retroviral transduction of FANCA significantly reduced MMC sensitivity but FANCF, FANCG, and FANCC did not. Overexpression of FANCA restored levels of both FANCA and FANCG, whereas overexpression of FANCG or FANCC did not restore FANCA levels. The molecular mass of cytoplasmic FANCA, FANCG, FANCC, and nuclear FANCD2 were normal. All exons of FANCA and FANCG were sequenced, and no mutations were found. We conclude that perturbations of as yet unidentified factors that govern the binding activity or intracellular localization of FANCA may promote cytogenetic instability and clonal progression in patients with AML who do not have Fanconi anemia.

Original languageEnglish (US)
Pages (from-to)7-16
Number of pages10
JournalBlood
Volume102
Issue number1
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

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Fanconi Anemia
Mitomycin
Acute Myeloid Leukemia
Cytogenetics
Fanconi Anemia Complementation Group Proteins
Bearings (structural)
Cells
Alkylating Agents
Molecular mass
Chromosomes
Stem cells
Exons
Myeloid Leukemia
Myeloid Cells
Chromosome Aberrations
Defects
Leukemia
Stem Cells
Clone Cells
Bone Marrow

ASJC Scopus subject areas

  • Hematology

Cite this

Lensch, M. W., Tischkowitz, M., Christianson, T. A., Reifsteck, C. A., Speckhart, S. A., Jakobs, P. M., ... Bagby, G. C. (2003). Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia. Blood, 102(1), 7-16. https://doi.org/10.1182/blood-2002-09-2781

Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia. / Lensch, M. William; Tischkowitz, Marc; Christianson, Tracy A.; Reifsteck, Carol A.; Speckhart, S. Ashley; Jakobs, Petra M.; O'Dwyer, Michael E.; Olson, Susan; Le Beau, Michelle M.; Hodgson, Shirley V.; Mathew, Chistopher G.; Larson, Richard A.; Bagby, Grover C.

In: Blood, Vol. 102, No. 1, 01.07.2003, p. 7-16.

Research output: Contribution to journalArticle

Lensch, MW, Tischkowitz, M, Christianson, TA, Reifsteck, CA, Speckhart, SA, Jakobs, PM, O'Dwyer, ME, Olson, S, Le Beau, MM, Hodgson, SV, Mathew, CG, Larson, RA & Bagby, GC 2003, 'Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia', Blood, vol. 102, no. 1, pp. 7-16. https://doi.org/10.1182/blood-2002-09-2781
Lensch MW, Tischkowitz M, Christianson TA, Reifsteck CA, Speckhart SA, Jakobs PM et al. Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia. Blood. 2003 Jul 1;102(1):7-16. https://doi.org/10.1182/blood-2002-09-2781
Lensch, M. William ; Tischkowitz, Marc ; Christianson, Tracy A. ; Reifsteck, Carol A. ; Speckhart, S. Ashley ; Jakobs, Petra M. ; O'Dwyer, Michael E. ; Olson, Susan ; Le Beau, Michelle M. ; Hodgson, Shirley V. ; Mathew, Chistopher G. ; Larson, Richard A. ; Bagby, Grover C. / Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia. In: Blood. 2003 ; Vol. 102, No. 1. pp. 7-16.
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AU - Jakobs, Petra M.

AU - O'Dwyer, Michael E.

AU - Olson, Susan

AU - Le Beau, Michelle M.

AU - Hodgson, Shirley V.

AU - Mathew, Chistopher G.

AU - Larson, Richard A.

AU - Bagby, Grover C.

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N2 - Myelodysplastic and leukemic stem cell clones that evolve in children and adults with Fanconi anemia universally bear complex cytogenetic abnormalities. The abnormalities are generally recurring deletions or chromosomal loss and involve precisely the same chromosomes with the same frequency as has been described in marrow cells from patients with secondary acute leukemia induced by alkylating agents. Reasoning that acquired Fanconi anemia protein dysfunction might contribute to cytogenetic instability in secondary acute myelogenous leukemia (AML) cells, we analyzed leukemic cells bearing characteristic complex cytogenetic defects obtained from a 68 year-old man whose lymphoblasts showed no evidence of Fanconi anemia. Unlike the lymphoblasts, this myeloid leukemia cell line (UoC-M1) was hypersensitive to mitomycin-C (MMC) and diepoxybutane (DEB) and exhibited a marked decrease in nuclear FANCA, FANCG, and FANCD2-L. Retroviral transduction of FANCA significantly reduced MMC sensitivity but FANCF, FANCG, and FANCC did not. Overexpression of FANCA restored levels of both FANCA and FANCG, whereas overexpression of FANCG or FANCC did not restore FANCA levels. The molecular mass of cytoplasmic FANCA, FANCG, FANCC, and nuclear FANCD2 were normal. All exons of FANCA and FANCG were sequenced, and no mutations were found. We conclude that perturbations of as yet unidentified factors that govern the binding activity or intracellular localization of FANCA may promote cytogenetic instability and clonal progression in patients with AML who do not have Fanconi anemia.

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