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It has been known that 12‐ O ‐tetradecanoyl phorbol‐13‐acetate‐inducible sequence 21 (TIS21), ortholog of human B‐cell translocation gene 2, regulates expansions of stage‐specific thymocytes and hematopoietic progenitors. In the present study, lineage‐negative (Lin − )/stem cell antigen‐1‐positive (Sca‐1 + )/c‐Kit +  (LSK) cell content was significantly elevated in bone marrow (BM) of TIS21‐knockout (TIS21 −/− ) female mice, suggesting 17β‐estradiol (E 2 )‐regulated progenitor expansion. E 2  induced DNA synthesis and cell proliferation of mouse embryonic fibroblasts (MEFs) isolated from TIS21 −/−  mice, but not wild type (WT). In contrast to WT, E 2  failed to activate protein kinase B (Akt) in the TIS21 −/−  MEFs, independent of extracellular signal‐regulated kinase 1/2 (Erk1/2) activation. Despite attenuation of Akt activation, mammalian target of rapamycin (mTOR) was constitutively activated in the TIS21 −/−  MEFs. Furthermore, mitogen‐activated protein kinase 1/2 inhibitor or knockdown of Erk1 could restore activation of Akt and downregulate mTOR. Immunoprecipitation showed Akt preferentially bound to phosphorylated Erk1/2 (p‐Erk1/2) in TIS21 −/−  cells, but reconstitution of TIS21 inhibited their interaction. E 2 ‐injected TIS21 −/−  male mice also increased LSK cells in BM. Taken together, expansion of hematopoietic progenitors in TIS21 −/−  female mice might be through inhibition of Akt activation, and constitutive activation of mTOR via preferential binding of TIS21 to E 2 ‐induced p‐Erk1/2, compared with that of Akt. Our results suggest that TIS21 plays a pivotal role in maintaining the hematopoietic stem cell compartment and hematopoiesis.  Disclosure of potential conflicts of interest is found at the end of this article.

stem cells

TIS21 /BTG2  Negatively Regulates Estradiol‐Stimulated Expansion of Hematopoietic Stem Cells by Derepressing Akt Phosphorylation and Inhibiting mTOR Signal Transduction