Abstract
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.
Highlights
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are heterogeneous clonal disorders characterized by the failure of normal hematopoiesis and the accumulation of immature or incompletely differentiated myeloid precursors [1, 2]
The majority of mixed-lineage leukemia 3 (MLL3) mutations seen in AML patients are truncating mutations that result in loss of the catalytic suppressor of variegation/enhancer of zeste/trithorax (SET) domain [6, 16, 44]
As these diseases both result from abnormal hematopoiesis and carry an increased incidence with age [1, 2], we investigated the effects of Mll3 loss-of-function on mature and progenitor populations in the bone marrow (BM) in a cohort of aged mice
Summary
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are heterogeneous clonal disorders characterized by the failure of normal hematopoiesis and the accumulation of immature or incompletely differentiated myeloid precursors [1, 2]. MDS is associated with dysplasia in myeloid lineages, peripheral cytopenias, and intramedullary cell death [1, 3], while AML is defined by the accumulation of blasts (>20%) in the bone marrow (BM) [2]. MDS and AML are among the most common myeloid malignancies, with up to 40% of MDS patients developing AML [2, 4]. Despite recent advances in therapeutics, such as azacitidine for MDS [5], the long-term survival rates for most of these patients are poor.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
