Deeply and widely understanding the regulation network of maintaining normal hematopoietic stem cell (HSC) function is essential for comprehending stem cell physiology and developing stem cell therapy such as stem cell transplantation, thus establishing appropriate therapeutic strategies for those patients suffered from leukemia and anemia. Here, we identified FAM122A as an essential factor for maintaining HSC homeostasis.
Family with sequence similarity 122A (FAM122A) is a human housekeeping gene localized on chromosome 9q21.1, and a highly conserved protein in many species of mammary animals. In 2016, we demonstrated for the first time that FAM122A interacts with the Aα and B55α subunits of protein phosphatase 2A (PP2A) and inhibits its phosphatase activity (1), which has been further confirmed by Li F et al in 2020 (2). Therefore, FAM122A is currently also designated as PP2A-Aα (PPP2R1A) and -B55α (PPP2R2A) interacting phosphatase regulator 1 (PABIR1).
Recently, we have found that FAM122A participates in multiple physiological and/or pathophysiological processes, including the regulation of erythrocyte differentiation (3), maintenance of DNA homeostasis (4) and the support of the growth of human hepatocellular carcinoma cells. FAM122A has also been found to be abnormally upregulated in acute myeloid leukemia (AML), and is essential for maintaining the growth of AML cells in vitro cultured cells and in vivo AML cell engraftment (5). Considering that AML is featured with the dysfunction of myeloid progenitors, in this study, we investigated whether FAM122A has a role in the function of HSCs. We found that Fam122a deletion in hematopoietic system causes the disruption of the quiescent state of long-term HSCs (LT-HSCs) with promoting their proliferation, and the skewing of differentiation in committed progenitors and T cells. More importantly, Fam122a deletion greatly impairs self-renewal capacity in a serial competitive transplantation, as assessed by hematopoietic-specific deletion of Fam122a mice with Vav-iCre and Mx1-Cre mice. Further, we found that Fam122a deletion significantly activates p38 MAPK signaling, an important negative regulator for maintaining the quiescence and restricting the cycling of HSCs. Collectively, our study demonstrates that FAM122A is a novel and critical regulator in HSC function.
(1) Fan L, Liu MH, Guo M, Hu CX, Yan ZW, Chen J, et al. FAM122A, a new endogenous inhibitor of protein phosphatase 2A. Oncotarget. 2016;7(39):63887-900.
(2) Li F, Kozono D, Deraska P, Branigan T, Dunn C, Zheng XF, et al. CHK1 inhibitor blocks phosphorylation of FAM122A and promotes replication stress. Mol Cell. 2020 Nov 5;80(3):410-422.
(3) Chen J, Zhou Q, Liu MH, Yang YS, Wang YQ, Huang Y, et al. FAM122A inhibits erythroid differentiation through GATA1. Stem Cell Reports. 2020 Sep 8;15(3):721-734.
(4) Wang YQ, Yang YS, Chen J, Liu MH, Chen GQ, Huang Y. FAM122A maintains DNA stability possibly through the regulation of topoisomerase IIα expression. Exp Cell Res. 2020 Nov 1;396(1):112242.
(5) Liu MH, Chen J, Yang YS, Wang YQ, Chen GQ, Zhang Y et al. FAM122A promotes acute myeloid leukemia cell growth through inhibiting PP2A activity and sustaining MYC expression. Haematologica. 2020 Apr 30:haematol. 2020.251462.