The acidic domain of Hmga2 and the domain’s linker region are critical for driving self-renewal of hematopoietic stem cell

Sun, Yuemei; Kubota, Sho; Iimori, Mihoko; Hamashima, Ai; Murakami, Haruka; Bai, Jie; Morii, Mariko; Yokomizo‐Nakano, Takako; Osato, Motomi; Araki, Kimi; Sashida, Goro

doi:10.1007/s12185-021-03274-9

Cited by 4 publications

(9 citation statements)

References 27 publications

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“…In comparison with WT HSCs, Hmga2 KI HSCs showed changes in the number of >2-fold differentially expressed genes (DEGs), such as the upregulated expression of Hmga2 and Igf2bp2 , a major target gene of Hmga2 in tissue stem cells (Li et al, 2012 ; Bai et al, 2021 ) (Dataset EV 1 ). Consistent with similar behaviors in hematopoiesis between WT and Hmga2 KI mice in the steady state (Sun et al, 2022 ), a principal component analysis (PCA) using the transcriptomes of all genes confirmed that Hmga2 KI HSCs were closer to WT HSCs in the steady state, while both adult HSCs were located far from highly-proliferative fetal HSCs separated by the first principal component (PC) (Fig. 3A ).…”

Section: Resultssupporting

confidence: 80%

“…We previously reported a Rosa26-flox-stop-flox-HA-Hmga2-eGFP conditional KI ( Hmga2 KI) mouse showing the inducible overexpression of Hmga2 mRNA in adult HSCs to a similar degree as that in fetal HSCs (Sun et al, 2022 ). A serial transplantation assay revealed that the overexpression of Hmga2 enhanced the competitive repopulating capacity of HSCs, but did not confer that property to multipotent progenitor (MPP) cells, while WT cells completely lost their repopulation capacity after transplantation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The overexpression of Hmga2 via a retrovirus vector or a transgene was shown to enhance the self-renewal capacity of adult HSCs and the megakaryocyte and erythroid differentiation in humans and mice under in vivo conditions (Copley et al, 2013 ; Rowe et al, 2016 ; Kumar et al, 2019 ), but was insufficient to induce leukemic transformation (Ikeda et al, 2011 ; Bai et al, 2021 ). We generated Rosa26 locus Hmga2 conditional knock-in (KI) mice and recently reported that the overexpression of Hmga2 enhanced the self-renewal capacity of adult HSCs and maintained their fitness in the bone marrow (BM) of both primary mice and transplanted mice (Sun et al, 2022 ), while lethal irradiation followed by BM transplantation induced the excessive replication of HSCs and systemic inflammation and subsequently depleted wild-type (WT) HSCs in the long term (Rodrigues-Moreira et al, 2017 ; Caiado et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions

Kubota,

Sun,

Morii

et al. 2024

EMBO J

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The molecular mechanisms governing the response of hematopoietic stem cells (HSCs) to stress insults remain poorly defined. Here, we investigated effects of conditional knock-out or overexpression of Hmga2 (High mobility group AT-hook 2), a transcriptional activator of stem cell genes in fetal HSCs. While Hmga2 overexpression did not affect adult hematopoiesis under homeostasis, it accelerated HSC expansion in response to injection with 5-fluorouracil (5-FU) or in vitro treatment with TNF-α. In contrast, HSC and megakaryocyte progenitor cell numbers were decreased in Hmga2 KO animals. Transcription of inflammatory genes was repressed in Hmga2-overexpressing mice injected with 5-FU, and Hmga2 bound to distinct regions and chromatin accessibility was decreased in HSCs upon stress. Mechanistically, we found that casein kinase 2 (CK2) phosphorylates the Hmga2 acidic domain, promoting its access and binding to chromatin, transcription of anti-inflammatory target genes, and the expansion of HSCs under stress conditions. Notably, the identified stress-regulated Hmga2 gene signature is activated in hematopoietic stem progenitor cells of human myelodysplastic syndrome patients. In sum, these results reveal a TNF-α/CK2/phospho-Hmga2 axis controlling adult stress hematopoiesis.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions

Kubota,

Sun,

Morii

et al. 2024

EMBO J

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“…This model shows moderate elevation of white blood cell (WBC), red blood cell (RBC), and platelet (PLT) counts, increased number and repopulating capacity of HSPCs as well as increased megakaryopoiesis; however, it does not develop lethal myeloid disease 89) . Hmga2 conditional knock-in mice reported from elsewhere were phenotypically similar to those with Hmga2 -Tg 90) . Of note, another model of HMGA2 -Tg mice that overexpresses human HMGA2 has been reported to develop very aggressive acute lymphoid leukemia 92) .…”

Section: The Role Of Hmga2 In Myeloid Malignanciessupporting

confidence: 63%

“…To clarify how HMGA2 contributes to disease progression, we and other groups generated several murine models that express external Hmga2 transgenes 89 , 90) or re-express endogenous HMGA2 by deletion of Ezh2 87 , 88 , 91) . A model of transgenic mice with a truncated murine Hmga2 ( Hmga2 -Tg, also described as Δ Hmga2 ) shows about 3- to 5-fold increased expression of HMGA2 compared to wild-type (WT) controls in hematopoietic tissues.…”

Section: The Role Of Hmga2 In Myeloid Malignanciesmentioning

confidence: 99%

Cellular carcinogenesis in preleukemic conditions:drivers and defenses

Ueda,

Ikeda

2024

FJMS

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Acute myeloid leukemia (AML) arises from preleukemic conditions. We have investigated the pathogenesis of typical preleukemia, myeloproliferative neoplasms, and clonal hematopoiesis. Hematopoietic stem cells in both preleukemic conditions harbor recurrent driver mutations ; additional mutation provokes further malignant transformation, leading to AML onset. Although genetic alterations are defined as the main cause of malignant transformation, nongenetic factors are also involved in disease progression. In this review, we focus on a nonhistone chromatin protein, high mobility group AT -hook2 (HMGA2), and a physiological p53 inhibitor, murine double minute X (MDMX). HMGA2 is mainly overexpressed by dysregulation of microRNAs or mutations in polycomb components, and provokes expansion of preleukemic clones through stem cell signature disruption. MDMX is overexpressed by altered splicing balance in myeloid malignancies. MDMX induces leukemic transformation from preleukemia via suppression of p53 and p53 -independent activation of WNT/βcatenin signaling. We also discuss how these nongenetic factors can be targeted for leukemia prevention therapy.

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Animal models for COVID-19: advances, gaps and perspectives

Fan

Xiong

et al. 2022

Sig Transduct Target Ther

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COVID-19, caused by SARS-CoV-2, is the most consequential pandemic of this century. Since the outbreak in late 2019, animal models have been playing crucial roles in aiding the rapid development of vaccines/drugs for prevention and therapy, as well as understanding the pathogenesis of SARS-CoV-2 infection and immune responses of hosts. However, the current animal models have some deficits and there is an urgent need for novel models to evaluate the virulence of variants of concerns (VOC), antibody-dependent enhancement (ADE), and various comorbidities of COVID-19. This review summarizes the clinical features of COVID-19 in different populations, and the characteristics of the major animal models of SARS-CoV-2, including those naturally susceptible animals, such as non-human primates, Syrian hamster, ferret, minks, poultry, livestock, and mouse models sensitized by genetically modified, AAV/adenoviral transduced, mouse-adapted strain of SARS-CoV-2, and by engraftment of human tissues or cells. Since understanding the host receptors and proteases is essential for designing advanced genetically modified animal models, successful studies on receptors and proteases are also reviewed. Several improved alternatives for future mouse models are proposed, including the reselection of alternative receptor genes or multiple gene combinations, the use of transgenic or knock-in method, and different strains for establishing the next generation of genetically modified mice.

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The acidic domain of Hmga2 and the domain’s linker region are critical for driving self-renewal of hematopoietic stem cell

Cited by 4 publications

References 27 publications

Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions

Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions

Cellular carcinogenesis in preleukemic conditions:drivers and defenses

Animal models for COVID-19: advances, gaps and perspectives

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