Loss of Mll3 catalytic function promotes aberrant myelopoiesis

Kelly M. Arcipowski, Marinka Bulic, Sandeep Gurbuxani, Jonathan D. Licht

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Two of the most commonmyeloid malignancies,myelodysplastic syndrome (MDS) and acutemyeloid 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 formof 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.

Original languageEnglish
Article numbere0162515
JournalPLoS ONE
Volume11
Issue number9
DOIs
StatePublished - Sep 2016
Externally publishedYes

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