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Leukemic survival factor SALL4 contributes to defective DNA damage repair

Oncogene volume 35, pages 6087–6095 (2016)Cite this article

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Abstract

SALL4 is aberrantly expressed in human myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We have generated a SALL4 transgenic (SALL4B Tg) mouse model with pre-leukemic MDS-like symptoms that transform to AML over time. This makes our mouse model applicable for studying human MDS/AML diseases. Characterization of the leukemic initiation population in this model leads to the discovery that Fancl (Fanconi anemia, complementation group L) is downregulated in SALL4B Tg leukemic and pre-leukemic cells. Similar to the reported Fanconi anemia (FA) mouse model, chromosomal instability with radial changes can be detected in pre-leukemic SALL4B Tg bone marrow (BM) cells after DNA damage challenge. Results from additional studies using DNA damage repair reporter assays support a role of SALL4 in inhibiting the homologous recombination pathway. Intriguingly, unlike the FA mouse model, after DNA damage challenge, SALL4B Tg BM cells can survive and generate hematopoietic colonies. We further elucidated that the mechanism by which SALL4 promotes cell survival is through Bcl2 activation. Overall, our studies demonstrate for the first time that SALL4 has a negative impact in DNA damage repair, and support the model of dual functional properties of SALL4 in leukemogenesis through inhibiting DNA damage repair and promoting cell survival.

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Acknowledgements

L Chai and W Cui designed the research, analyzed data and wrote the paper. F Wang and C Gao performed the research experiments, analyzed data and wrote the paper. J Lu and H Tatetsu performed the research experiments and analyzed the data. D Williams provided Fanca−/− mice and edited the paper. L Muller performed Fanca−/− mice related experiments. We also want to thank Dr S Xiao for providing DNA repair reporter plasmids, X Yao, and D Neuberg for statistic analysis, X Tian in assisting animal work, and N Kong in editing of the manuscript. This work was supported in part through NIH R03CA184531 and PO1HL095489, funding from Lymphoma and Leukemia Society (No. SLP-8004-14 and TRP-6482-16) and V cancer research Foundation (to L Chai), by the National Natural Science Foundation of China (NSFC) - 81071418 and 81472029 (to W Cui), and China Scholarship Council (No.201206210154) (to F Wang).

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Author notes

  1. F Wang and C Gao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Joint Program in Transfusion Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    F Wang, C Gao, J Lu, H Tatetsu & L Chai

  2. Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    F Wang & W Cui

  3. Division of Hematology/Oncology, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA

    D A Williams & L U Müller

  4. Genentech, South San Francisco, CA, USA

    L U Müller

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Correspondence to W Cui or L Chai.

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Wang, F., Gao, C., Lu, J. et al. Leukemic survival factor SALL4 contributes to defective DNA damage repair. Oncogene 35, 6087–6095 (2016). https://doi.org/10.1038/onc.2016.146

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