{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T13:22:40Z","timestamp":1791465760535,"version":"4.3.4"},"reference-count":58,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,2,26]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Sickle cell disease (SCD) and \u03b2-thalassemia are devastating genetic disorders resulting from defects in the \u03b2-globin subunit of adult hemoglobin. Both disorders are ameliorated by the induction of \u03b3-globin, a component of fetal hemoglobin (HbF). Therefore, the development of safe, effective, and widely available inducers of HbF is needed. Here, we discovered that slow cycling erythroid cells exhibit increased \u03b3-globin expression. To understand the molecular basis of this, we screened all cyclin-dependent kinase inhibitors (CDKIs) for their ability to induce HbF using CRISPR activation. We found that overexpression of CDKN1B, which encodes p27Kip1 (but not overexpression of other CDKIs), induces \u03b3-globin expression at the transcriptional level. CDKN1B mutants expressing proteins unable to bind\/inhibit CDKs and\/or cyclins revealed that \u03b3-globin induction by p27Kip1 depends largely on the domains involved in its cell cycle function. Pharmacological inhibition and genetic reduction of CDK4\/6 also result in increased HbF. In genetic rescue experiments, we show that p27Kip1 induces HbF by inhibiting CDK4\/6, through a mechanism that is likely BCL11A and ZBTB7A independent. Furthermore, palbociclib, an oral CDK4\/6 inhibitor, significantly increases HbF in a murine SCD model at doses that are well tolerated. Moreover, we show that HbF induction by hydroxyurea, a drug currently in use to treat SCD, may be mediated in part by CDK4\/6 inhibition. Overall, our findings establish a causal relationship between CDK4\/6 activity and \u03b3-globin production and suggest that single or dual CDK4\/6 inhibitors might be therapeutically beneficial for SCD and \u03b2-thalassemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025028895","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T17:36:33Z","timestamp":1766079393000},"page":"973-986","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":3,"title":["p27Kip1 regulates \u03b3-globin production"],"prefix":"10.1182","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1062-6774","authenticated-orcid":false,"given":"Ginette","family":"Balbin-Cuesta","sequence":"first","affiliation":[{"name":"1Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI"},{"name":"2Medical Scientist Training Program, University of Michigan, Ann Arbor, 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