Loss of Mll3 Catalytic Function Promotes Aberrant Myelopoiesis.
Two of the most common myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), are associated with exceedingly low survival rates despite recent therapeutic advances. While their etiology is not completely understood, evidence suggests that certain chromosomal abnormalities contribute to MDS and AML progression. Among the most frequent chromosomal abnormalities in these disorders are alterations of chromosome 7: either complete loss of one copy of chromosome 7 (-7) or partial deletion of 7q (del(7q)), both of which increase the risk of progression from MDS to AML and are associated with chemoresistance. Notably, 7q36.1, a critical minimally deleted region in 7q, includes the gene encoding the histone methyltransferase mixed-lineage leukemia 3 (MLL3), which is also mutated in a small percentage of AML patients. However, the mechanisms by which MLL3 loss contributes to malignancy are unknown. Using an engineered mouse model expressing a catalytically inactive form of Mll3, we found a significant shift in hematopoiesis toward the granulocyte/macrophage lineage, correlating with myeloid infiltration and enlargement of secondary lymphoid organs. Therefore, we propose that MLL3 loss in patients may contribute to the progression of MDS and AML by promoting myelopoiesis.
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Kelly M
KM
Arcipowski
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Marinka
M
Bulic
Department of Clinical Hematology/Hematopathology, University of Chicago Medical Center, Chicago, Illinois, United States of America.
Sandeep
S
Gurbuxani
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.|The University of Florida Health Cancer Center, Gainesville, Florida, United States of America.
Jonathan D
http://orcid.org/0000-0002-3942-1369
JD
Licht
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D033481:Chromosomes, Mammalian / Q000235:genetics; D005434:Flow Cytometry; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D051379:Mice; D038042:Myelopoiesis / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D004268:DNA-Binding Proteins
D011495:Histone-Lysine N-Methyltransferase; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins