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Human NUP98-IQCG fusion protein induces acute myelomonocytic leukemia in mice by dysregulating the Hox/Pbx3 pathway

Leukemia volume 30, pages 1590–1593 (2016)Cite this article

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The NUP98 gene located at chromosome 11p15 has been reported to fuse with ~34 different partner genes by chromosome translocations in hematological malignancies. Numerous NUP98 fusions alter the gene expression profiles of normal hematopoietic stem and progenitor cells; this alteration is characterized by overexpression of several HOXA cluster genes, which is associated with poor prognosis in acute myeloid leukemia. Several bone marrow transplantation (BMT) mouse models have shown that overexpression of select HOX genes, such as HOXA9, HOXA10, HOXB3 or HOXB6, can induce long-latency leukemia, and both MEIS1 and PBX3 can potentiate the leukemogenic effect of HOX effectively.1, 2, 3, 4, 5, 6 NUP98-IQ motif containing G (IQCG) was identified in a myeloid/T-lymphoid bi-phenoleukemia patient with t(3;11)(q29q13;p15),del(3)(q29),+21, which was confirmed as a somatic karyotype.7, 8 However, the leukemogenic ability of NUP98-IQCG has not fully been clarified.

After transplantation, 13 of the 18 mice in NUP98-IQCG group succumbed within 14 months with a median survival of 326 days (Figure 1d). In contrast, all control mice remained disease free during the observation period. Hematologic examinations revealed the high peripheral white blood cell counts with significantly increased amounts of promonocytes (indicated by arrow in Figure 1e) in diseased NUP98-IQCG mice (Figure 1f and Supplementary Figures S1a and b). This finding was further confirmed by histochemical staining. Non-specific alpha-naphthyl acetate esterase assay showed that leukemic blasts exhibit intense diffuse granulation in the cytoplasm, which could be inhibited by sodium fluoride (inhibition rate, 84%, Supplementary Figure S1f). The immunophenotype of BM cells through flow cytometry (FCM) also found a significant increase in Mac-1+Gr-1−/low monocytes and c-Kit+Mac-1+/low immature myeloid cells in the NUP98-IQCG group (Figure 1g and Supplementary Figures S2a and b). These results suggest that mice transplanted with fusion gene-expressing cells ultimately develop acute myelomonocytic leukemia. Moreover, these leukemic mice developed massive splenomegaly and moderate hepatomegaly (Supplementary Figures S1a and c). The infiltration of leukemia cells caused serious damage to the spleen, and the characteristics of leukemia cell were similar to those found in BM (Supplementary Figures S1e and S2c). Both mRNA and protein expression levels of NUP98-IQCG in BM samples were detected, thereby validating the model (Supplementary Figure S1d).

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Acknowledgements

We appreciate Shu-Ming Xiong and Bing Chen (Rui Jin Hospital affiliated to SJTU School of Medicine) for hematologic morphological and cytogenetic analysis. We thank Hong Lu (Shanghai Institute of Digestive Diseases, Shanghai Ren ji Hospital, SJTU School of Medicine) and Jing Yi (Department of Cell Biology, Basic Medical College, SJTU School of Medicine) for kindly providing the luciferase reporter vectors. This work was supported by the Chinese National Key Basic Research Project 973 Grant 2013CB966800, Ministry of Health Grant 201202003, the Mega-projects of Scientific Research for the 12th Five-Year Plan Grant 2013ZX09303302, the National High Tech Program for Biotechnology Grant 863 (2012AA02A505), the State Key Laboratories Project of Excellence Grant 81123005, the National Natural Science Foundation of China Grants 81222004 and 81170506, and the Samuel Waxman Cancer Research Foundation Co-PI Program.

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  1. M M Pan and Q Y Zhang: These authors contributed equally to this work.

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  1. State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University (SJTU) School of Medicine, Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China

    M M Pan, Q Y Zhang, Y Y Wang, P Liu, R B Ren, J Y Huang, L T Chen, X D Xi, Z Chen & S J Chen

  2. Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences and (SJTU) School of Medicine, Shanghai, China

    Q Y Zhang, Z Chen & S J Chen

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Pan, M., Zhang, Q., Wang, Y. et al. Human NUP98-IQCG fusion protein induces acute myelomonocytic leukemia in mice by dysregulating the Hox/Pbx3 pathway. Leukemia 30, 1590–1593 (2016). https://doi.org/10.1038/leu.2015.347

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