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ANIMAL MODELS

Trib1 promotes the development of acute myeloid leukemia in a Ts1Cje mouse model of Down syndrome

Leukemia volume 36, pages 558–561 (2022)Cite this article

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Down syndrome (DS), caused by the trisomy of chromosome 21, is the most common genetic disorder worldwide, affecting ~1 in 700 live births. Individuals with DS exhibit various clinical manifestations, including intellectual disability, cardiovascular malformations, facial dysmorphia, immunodeficiency, and predisposition to hematopoietic neoplasms. Approximately 10% of children with DS show clinical manifestation of transient myeloproliferative disorder (TMD), characterized by a significant increase in immature megakaryoblasts [1]. Normally, TMD spontaneously regresses within a month; however, 30% of patients with TMD subsequently develop acute megakaryocytic leukemia (DS-AMKL) afterwards [1, 2]. Moreover, individuals with DS show a predisposition to develop acute B-lymphoblastic leukemia, suggesting that trisomy 21 is an important risk factor for leukemia development [2]. The development of TMD is associated with acquired GATA1 mutations in almost all cases [3, 4]. Comprehensive genomic analysis of DS-AMKL has identified recurrent somatic mutations in several genes including CCCTC-binding factor, enhancer of zeste 2 polycomb repressive complex 2 subunit, neuroblastoma RAS viral oncogene homolog, stromal antigen 2, and RAD21 cohesin complex component [5], indicating that the GATA1 mutations may not be the only cause of DS-AMKL development.

We have previously identified a gain-of-function mutation in tribbles pseudokinase 1 (TRIB1), a pseudokinase protein that acts as a molecular adaptor, in a case of DS-AMKL [6]. TRIB1 recruits an E3 ubiquitin ligase constitutive photomorphogenesis 1 protein (COP1) to degrade the myeloid tumor suppressor C/EBPα, and at a same time, it interacts with MEK1 to sustain phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) [7]. The detected TRIB1 R107L mutation promotes both the degradation of C/EBPα and the enhancement of MEK/ERK signaling, although this mutation is rare in DS-AMKL and has not been identified in the other TMD and DS-AMKL patients [7, 8]. These results suggest that combined with trisomy 21, TRIB1-mediated signaling may be involved in the development of DS-associated myeloid leukemia.

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Fig. 1: Trib1 promoted the development of AML in Ts1Cje mice.
Fig. 2: Transcriptome analysis of Trib1-induced mouse leukemic cells and human DS-AMKL.

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Acknowledgements

The microarray data are available in the NCBI Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE168531. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant nos. 19H01035 to TN and 20K16318 to SY), a grant from the Vehicle Racing Commemorative Foundation (to MT, TM, and KI), Cyclic Innovation for Clinical Empowerment from Japan Agency for Medical Research and Development (grant no. 18pc0101033h001 to TN), and a grant from the Uehara Memorial Foundation (to SY).

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Authors and Affiliations

  1. Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    Seiko Yoshino, Miwa Tanaka, Yoshitaka Sunami, Tomoko Takahara, Yukari Yamazaki, Mizuki Homme & Takuro Nakamura

  2. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Akiko Niibori-Nambu & Motomi Osato

  3. Division of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto, Japan

    Takashi Minami

  4. Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Kyoto, Japan

    Keiichi Ishihara

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  1. Seiko Yoshino
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Correspondence to Takuro Nakamura.

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Yoshino, S., Tanaka, M., Sunami, Y. et al. Trib1 promotes the development of acute myeloid leukemia in a Ts1Cje mouse model of Down syndrome. Leukemia 36, 558–561 (2022). https://doi.org/10.1038/s41375-021-01384-1

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