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Unraveling the role of FANCD2 in chronic myeloid leukemia

Leukemia volume 26, pages 1447–1448 (2012)Cite this article

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Recent studies have offered new clues to understand the role of the Fanconi anemia (FA) pathway in the etiology and the progression of sporadic cancer (reviewed in Lyakhovich and Surralles1 and Valeri et al.2) This is particularly true in the case of chronic myeloid leukemia (CML), where two different studies have recently shown the role of FANCD2, a critical protein in the FA pathway, in the genetic instability3 and the leukemogenesis4 induced by the BCR-ABL1 oncogene.

Using human hematopoietic cells of different origin, our data showed that BCR-ABL1 inhibits the formation of FANCD2 nuclear foci, but not the expression nor the monoubiquitination of this protein, either spontaneously or after exposure to DNA cross-linking drugs, such as mitomycin C (MMC).3 Although the inhibited formation of FANCD2 foci in cells from CML patients or from the BCR-ABL1-transfected megakaryoblastic leukemia Mo7e cell line could be a consequence of secondary events related to the genetic instability of these cells, our data in fresh cord blood CD34+ (CB-CD34+) cells transduced with the MIN210 retroviral vector are of particular relevance, as they directly implicate the BCR-ABL1 oncogene in the inhibited formation of FANCD2 foci in primary human hematopoietic stem/progenitor cells. In that study, we also showed that both the impaired formation of FANCD2 nuclear foci and also the centrosomal and chromosomal aberrations—measured by chromatid-type breakages—induced by BCR-ABL1, were significantly reverted by the ectopic expression of BRCA1, in good consistency with previous data showing a downregulated expression of BRCA1 by the BCR-ABL1 oncoprotein.5, 6 Our results evidenced for the first time that a disruption of the FA/BRCA pathway in BCR-ABL1 cells—in particular the impaired formation of nuclear FANCD2 foci—should have an important role in the genomic instability of CML by the co-occurrence of centrosomal amplification and DNA repair deficiencies.

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Authors and Affiliations

  1. Hematopoiesis and Gene Therapy Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    A Valeri, P Río & J A Bueren

  2. Fundación para la Investigación Médica Aplicada (CIMA), Clínica Universidad de Navarra, Pamplona, Spain

    X Agirre & F Prosper

Authors
  1. A Valeri
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  2. P Río
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  3. X Agirre
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  4. F Prosper
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  5. J A Bueren
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Correspondence to J A Bueren.

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The authors declare no conflict of interest.

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Valeri, A., Río, P., Agirre, X. et al. Unraveling the role of FANCD2 in chronic myeloid leukemia. Leukemia 26, 1447–1448 (2012). https://doi.org/10.1038/leu.2012.32

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