A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia
Mohamed Eldeeb,
Ouyang Yuan,
Nicola Guzzi,
Phuong Cao Thi Ngoc,
Anna Konturek-Ciesla,
Trine A. Kristiansen,
Sowndarya Muthukumar,
Jeffrey Magee,
Cristian Bellodi,
Joan Yuan,
David Bryder
Affiliations
Mohamed Eldeeb
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
Ouyang Yuan
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
Nicola Guzzi
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
Phuong Cao Thi Ngoc
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
Anna Konturek-Ciesla
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
Trine A. Kristiansen
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
Sowndarya Muthukumar
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
Jeffrey Magee
Division of Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
Cristian Bellodi
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
Joan Yuan
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
David Bryder
Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden; Corresponding author
Summary: MLL-rearrangements (MLL-r) are recurrent genetic events in acute myeloid leukemia (AML) and frequently associate with poor prognosis. In infants, MLL-r can be sufficient to drive transformation. However, despite the prenatal origin of MLL-r in these patients, congenital leukemia is very rare with transformation usually occurring postnatally. The influence of prenatal signals on leukemogenesis, such as those mediated by the fetal-specific protein LIN28B, remains controversial. Here, using a dual-transgenic mouse model that co-expresses MLL-ENL and LIN28B, we investigate the impact of LIN28B on AML. LIN28B impedes the progression of MLL-r AML through compromised leukemia-initiating cell activity and suppression of MYB signaling. Mechanistically, LIN28B directly binds to MYBBP1A mRNA, resulting in elevated protein levels of this MYB co-repressor. Functionally, overexpression of MYBBP1A phenocopies the tumor-suppressor effects of LIN28B, while its perturbation omits it. Thereby, we propose that developmentally restricted expression of LIN28B provides a layer of protection against MYB-dependent AML.
