| First Author | Nakamae I | Year | 2017 |
| Journal | Blood Adv | Volume | 1 |
| Issue | 20 | Pages | 1682-1693 |
| PubMed ID | 29296815 | Mgi Jnum | J:385283 |
| Mgi Id | MGI:8331147 | Doi | 10.1182/bloodadvances.2017007054 |
| Citation | Nakamae I, et al. (2017) Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPalpha to prevent Trib1-driven acute myeloid leukemia. Blood Adv 1(20):1682-1693 |
| abstractText | C/EBPalpha is a key transcription factor regulating myeloid differentiation and leukemogenesis. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPalpha for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). Here we show that myeloid leukemia factor 1 (MLF1) stabilizes C/EBPalpha protein levels by inhibiting the ligase activity of the Trib1-COP1 complex. MLF1 directly interacts with COP1 in the nucleus and interferes with the formation of the Trib1-COP1 complex, thereby blocking its ability to polyubiquitinate C/EBPalpha for degradation. MLF1 overexpression suppressed the Trib1-induced growth advantage in a murine bone marrow (BM) culture and Trib1-induced AML development in BM-transplanted mouse models. MLF1 was expressed in hematopoietic stem cells and myeloid progenitors (common myeloid progenitors and granulocyte-macrophage progenitors) in normal hematopoiesis, which is consistent with the distribution of C/EBPalpha. An MLF1 deficiency conferred a more immature phenotype on Trib1-induced AML development. A higher expression ratio of Trib1 to MLF1 was a key determinant for AML development in mouse models, which was also confirmed in human patient samples with acute leukemia. These results indicate that MLF1 is a positive regulator that is critical for C/EBPalpha stability in the early phases of hematopoiesis and leukemogenesis. |
