FAM122A is required for hematopoietic stem cell function

Liu, Man-Hua; Zhang, Xiao-Cui; Chen, Jing; Yang, Yunsheng; Wang, Yin-Qi; Zheng, Junke; Chen, Guoqiang; Huang, Ying

doi:10.1038/s41375-020-01099-9

Cited by 6 publications

(5 citation statements)

References 16 publications

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“…Fam122a floxed mice were produced by Shanghai Renyuan Biotechnology as described previously. 24 Myh6 -Cre mice were purchased from Shanghai Model Organisms Center, Inc., and Nkx2-5 -Cre mice were bought from Jiangsu Gempharmatech Biotechnology. Fam122a conditional KO mice were on a C57BL/6 background.…”

Section: Methodsmentioning

confidence: 99%

“…FAM122A knockout (KO) suppresses the growth of hepatocellular carcinoma cells and acute myeloid leukemia cells in vitro and in vivo, with independence or dependence of PP2A inhibitory activity. 22 , 23 In addition, FAM122A is essential for maintaining the self-renewal capability of hematological stem cells 24 and required for the differentiation of erythroid cells; 25 FAM122A also contributes to the maintenance of DNA stability in malignant tumor cells. 26 These studies suggest that FAM122A has multifaceted functions under physiological or pathological circumstances.…”

Section: Introductionmentioning

confidence: 99%

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FAM122A Is Required for Mesendodermal and Cardiac Differentiation of Embryonic Stem Cells

et al. 2023

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Mesendodermal specification and cardiac differentiation are key issues for developmental biology and heart regeneration medicine. Previously, we demonstrated that FAM122A, a highly conserved house-keeping gene, is an endogenous inhibitor of protein phosphatase 2A (PP2A) and participates in multifaceted physiological and pathological processes. However, the in vivo function of FAM122A is largely unknown. In this study, we observed that Fam122 deletion resulted in embryonic lethality with severe defects of cardiovascular developments and significantly attenuated cardiac functions in conditional cardiac-specific knockout mice. More importantly, Fam122a deficiency impaired mesendodermal specification and cardiac differentiation from mouse embryonic stem cells but showed no influence on pluripotent identity. Mechanical investigation revealed that the impaired differentiation potential was caused by the dysregulation of histone modification and Wnt and Hippo signaling pathways through modulation of PP2A activity. These findings suggest that FAM122A is a novel and critical regulator in mesendodermal specification and cardiac differentiation. This research not only significantly extends our understanding of the regulatory network of mesendodermal/cardiac differentiation but also proposes the potential significance of FAM122A in cardiac regeneration.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FAM122A Is Required for Mesendodermal and Cardiac Differentiation of Embryonic Stem Cells

et al. 2023

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“…Emerging evidence also shows that quiescence preserves HSC functions by preventing DNA damage, senescence, and mutation. Intracellular and extracellular ingredients such as products of metabolism, cytokines, transcriptional factors, and chromatin remodelers have been reported to restrict HSCs in the quiescent state 19–29 . However, there still lacks precise methods to regulate the quiescent state of HSCs.…”

Section: Introductionmentioning

confidence: 99%

“…Intracellular and extracellular ingredients such as products of metabolism, cytokines, transcriptional factors, and chromatin remodelers have been reported to restrict HSCs in the quiescent state. [19][20][21][22][23][24][25][26][27][28][29] However, there still lacks precise methods to regulate the quiescent state of HSCs.…”

Section: Introductionmentioning

confidence: 99%

Near-Infrared Dye Ir-780 Alleviates Hematopoietic System Damage by Promoting Hematopoietic Stem Cells Into Quiescence

Wu,

Ma,

Gong

et al. 2024

Shock

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Worrying about potential radiation exposure is a general concern, but no effective pre-exposure radioprotective countermeasure is generally accepted1. Here, we found a small molecular near-infrared (NIR) dye IR-780, which promoted hematopoietic stem cells (HSCs) into quiescence to resist stress. When mice were treated with IR-780 before stress, increased HSC quiescence and better hematopoietic recovery were observed in IR-780-treated mice in stress conditions. However, when given after radiation, IR-780 did not show obvious benefit. Transplantation assay and colony-forming assay were carried out to determine self-renewal ability and repopulation capacity. Furthermore, IR-780 reduced the generation of reactive oxygen species (ROS) and DNA damage in HSCs after radiation. In homeostasis, the percentage of Lineage-, Sca-1+, and c-Kit+ cells (LSKs) and long-term HSCs (LT-HSCs) were improved, and more HSCs were in G0 state after administration of IR-780. Further investigations showed that IR-780 selectively accumulated in LT-HSCs with high mitochondria membrane potential (MMP) and entered cells by organic anion transporting polypeptides 1b2(Oatp1b2). Finally, IR-780 promoted human CD34+ hematopoietic stem cell reconstruction ability in NOD-PrkdcscidIl2rgnull (NSG) mice after transplantation and improved repopulation capacity in vitro culture. Our research showed that IR-780 selectively entered MMP-high LT-HSCs and promoted them into dormancy, thus reducing hematopoietic injury and improving regeneration capacity. This novel approach might hold promise as a potential radiation countermeasure.

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“…Hematopoietic stem cells (HSCs) sustain production of multiple blood lineages throughout their lifetime, whereas leukemia stem cells (LSCs) are responsible for initiation and propagation of leukemia and significantly related to therapy failure and recurrence of the malignancies. [1][2][3][4] Chronic myelogenous leukemia (CML) results from malignant transformation of HSCs by the BCR-ABL1 oncogene, which is generated by t(9;22) chromosome translocation. 5 Tyrosine kinase inhibitors (TKIs) are highly effective in inducing remission of patients with CML, but they fail to target LSCs of CML, and recurrence is commonly seen following discontinuation of TKI treatment.…”

Section: Introductionmentioning

confidence: 99%

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

Yang

Zhu

Zhang³

et al. 2021

Blood

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Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell-specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and post-injury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from chronic myelogenous leukemia (CML) patients. Anp32b deletion enhances p53 transcriptional activity to impair LSCs function in a murine CML model, and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B, and identify ANP32B as a potential therapeutic target in treating CML.

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FAM122A is required for hematopoietic stem cell function

Cited by 6 publications

References 16 publications

FAM122A Is Required for Mesendodermal and Cardiac Differentiation of Embryonic Stem Cells

FAM122A Is Required for Mesendodermal and Cardiac Differentiation of Embryonic Stem Cells

Near-Infrared Dye Ir-780 Alleviates Hematopoietic System Damage by Promoting Hematopoietic Stem Cells Into Quiescence

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

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