ArticleBlood2013
MLL fusion protein-driven AML is selectively inhibited by targeted disruption of the MLL-PAFc interaction.
Article in Blood, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- A chemical-genetic interaction between PAF1 and ENL/AF9 YEATS inhibition.RSC chemical biology · 2026Article
- The YEATS domain epigenetic reader proteins ENL and AF9 and their therapeutic value in leukemia.Experimental hematology · 2023Review
- The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia.Leukemia · 2023Article
- Mutational landscape and clinical outcome of pediatric acute myeloid leukemia with 11q23/KMT2A rearrangements.Cancer medicine · 2023Article
- The role of E2A in ATPR-induced cell differentiation and cycle arrest in acute myeloid leukaemia cells.Journal of cellular and molecular medicine · 2022Article
- Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.Nature communications · 2021Article
- Structure, function and inhibition of critical protein-protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins.Journal of hematology & oncology · 2021Review
- The PAF1c Subunit CDC73 Is Required for Mouse Hematopoietic Stem Cell Maintenance but Displays Leukemia-Specific Gene Regulation.Stem cell reports · 2019Article
- PAF1 complex interactions with SETDB1 mediate promoter H3K9 methylation and transcriptional repression ofOncotarget · 2018Article
- The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia.Oncogene · 2018Article
- LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis.Blood · 2018Article
- Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.Leukemia · 2015Article
- Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia.Experimental hematology · 2014Review
- Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal.Blood · 2014Article
- Epigenetic control of gene expression in leukemogenesis: Cooperation between wild type MLL and MLL fusion proteins.Molecular & cellular oncologyReview
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
MLL rearrangements are common in leukemia and considered an adverse risk factor. Through interactions with the polymerase-associated factor complex (PAFc), mixed lineage leukemia (MLL) fusion proteins activate genes critical for blocking differentiation, such as HOXA9. Here we investigate whether the MLL-PAFc interaction can be exploited therapeutically using both genetic and biochemical approaches. We tested the genetic requirement of the PAFc in acute myeloid leukemia (AML) using a conditional allele of the PAFc subunit, Cdc73. We show that the PAFc is indiscriminately necessary for the proliferation of AML cells through the epigenetic regulation of proleukemogenic target genes, such as MEIS1 and Bcl2. To investigate the therapeutic potential of targeting the MLL-PAFc interaction, we engineered a dominant negative fragment of MLL capable of binding to the PAFc. Disruption of the MLL-PAFc interaction selectively inhibits the proliferation of MLL leukemic cells without affecting cells transformed by an unrelated E2A-HLF fusion protein. Using in vivo hematopoietic reconstitution assays, we demonstrate that disruption of the MLL-PAFc does not alter normal hematopoietic stem cell function. Together, our data show a selective growth inhibition of MLL-associated leukemic cells and tolerance of normal hematopoiesis to disruption of the MLL-PAFc interaction establishing the MLL-PAFc interaction as an attractive therapeutic target.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.