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Acute Leukemias

A novel Leu153Ser mutation of the Fanconi anemia FANCD2 gene is associated with severe chemotherapy toxicity in a pediatric T-cell acute lymphoblastic leukemia

Leukemia volume 21, pages 72–78 (2007)Cite this article

Abstract

Fanconi anemia (FA) is an autosomal recessive disease characterized by pancitopenia, congenital malformations, predisposition to cancers and chromosomal instability. We report the clinical and molecular features of a patient initially identified as a potential FA case only because of chemotherapy toxicity during the treatment of a T-lineage acute lymphoblastic leukemia (ALL). Cells from this patient showed a moderate chromosomal instability, increasing sensitivity to DNA crosslinking agents but normal response to ionizing radiation. The analysis of FA proteins demonstrated a marked reduction of FANCD2 (>95%), but normal levels of FANCA or FANCG. Interestingly, this defect was associated with a homozygous missense mutation of FANCD2, resulting in a novel amino-acid substitution (Leu153Ser) at residue Leu153, which is highly conserved through evolution. The FANCD2L153S protein, whose reduced expression was not due to impaired transcription, was detected also in its monoubiquitinated form in the nucleus, suggesting that the mutation does not affect post-translation modifications or subcellular localization but rather the stability of FANCD2. Therefore, the hypomorphic Leu153Ser mutation represents the first example of a FANCD2 defect that might promote clonal progression of tumors, such as T-ALL, and severe chemotherapy toxicity in patients without any clinical manifestations typical of FA.

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Acknowledgements

We thank Enrico Fontanella for technical support of experimental procedures DNA damage response. This work was supported by grants of the Italian Association of Cancer Research (AIRC), the Italian Ministry of University and Scientific Research, the Italian Ministry of Health and the Fondazione Guido Berlucchi.

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics ‘F Cedrangolo’ II University of Naples, Naples, Italy

    A Borriello, M Criscuolo, V Cucciolla & F Della Ragione

  2. Bone Marrow Transplantation Centre, ‘S Camillo – Forlanini’ Hospital, Rome, Italy

    A Locasciulli

  3. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

    A M Bianco & V Conti

  4. Department of Experimental Medicine and Pathology, University ‘La Sapienza’ of Rome, Rome, Italy

    P Grammatico & S Cappellacci

  5. Department of Genetics, ‘Elena d'Aosta Hospital’, ASL Napoli 1, Naples, Italy

    A Zatterale

  6. Department of Reproductive and Developmental Sciences, Medical Genetics, IRCCS Burlo Garofolo Hospital, University of Trieste, Trieste, Italy

    F Morgese & A Savoia

  7. Department of Experimental Oncology, National Institute of Cancer, Milan, Italy

    D Delia

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  1. A Borriello
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Correspondence to A Savoia.

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Borriello, A., Locasciulli, A., Bianco, A. et al. A novel Leu153Ser mutation of the Fanconi anemia FANCD2 gene is associated with severe chemotherapy toxicity in a pediatric T-cell acute lymphoblastic leukemia. Leukemia 21, 72–78 (2007). https://doi.org/10.1038/sj.leu.2404468

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  • DOI: https://doi.org/10.1038/sj.leu.2404468

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