| RRC ID |
90112
|
| Author |
Han Y, Gudmundsdottir B, Gudmundsson KO, Roy KR, Tisdale J, Du Y.
|
| Title |
The histone methyltransferase MLL1 complex inhibits expression of fetal hemoglobin.
|
| Journal |
J Biol Chem
|
| Abstract |
Increasing fetal-type hemoglobin expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and β-thalassemia. We have identified the MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in γ- and ε-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A was readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of the MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34+ hematopoietic stem and progenitor cells induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their γ- and ε-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. Moreover, treatment of CD34+ hematopoietic stem and progenitor cells from SCD patients with MENIN inhibitors substantially increased γ-globin expression in their erythroid progenies. These findings underscore a critical role of the MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for SCD and β-thalassemia.
|
| Volume |
301(12)
|
| Pages |
110863
|
| Published |
2025-12-1
|
| DOI |
10.1016/j.jbc.2025.110863
|
| PII |
S0021-9258(25)02715-2
|
| PMID |
41161385
|
| PMC |
PMC12670561
|
| MeSH |
Anemia, Sickle Cell / genetics
Anemia, Sickle Cell / metabolism
Anemia, Sickle Cell / pathology
Antigens, CD34 / metabolism
Carrier Proteins* / genetics
Carrier Proteins* / metabolism
Cell Differentiation
Erythroid Cells / metabolism
Fetal Hemoglobin* / biosynthesis
Fetal Hemoglobin* / genetics
Fetal Hemoglobin* / metabolism
Gene Expression Regulation*
Gene Knockdown Techniques
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / metabolism
Histone-Lysine N-Methyltransferase* / genetics
Histone-Lysine N-Methyltransferase* / metabolism
Humans
Myeloid-Lymphoid Leukemia Protein* / genetics
Myeloid-Lymphoid Leukemia Protein* / metabolism
Nuclear Proteins* / genetics
Nuclear Proteins* / metabolism
Proto-Oncogene Proteins* / antagonists & inhibitors
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism
Repressor Proteins
beta-Thalassemia / genetics
beta-Thalassemia / metabolism
gamma-Globins / biosynthesis
gamma-Globins / genetics
|
| Resource |
| Human and Animal Cells |
HUDEP-2(RCB4557) |
