Tip60-mediated acetylation of H2A.Z activates Hoxa9 and Meis1 expression to promote MLL-rearranged acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA597547 | ENA |
REPOSITORIES: ENA
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Project description:Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biological characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias utilizing RNAi. Gene expression profiling after HOXA9 suppression demonstrated co-downregulation of a program highly expressed in human MLL-AML (this study) and murine MLL-leukemia (Krivtsov et al. 2006) stem cells including HOXA10, MEIS1, PBX3 and MEF2C. Our data indicates an important role for HOXA9 in human MLL-rearranged leukemias, and suggests targeting HOXA9 or downstream programs may be a novel therapeutic option.
2009-01-01 | GSE13714 | GEO
Project description:Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biological characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias utilizing RNAi. Gene expression profiling after HOXA9 suppression demonstrated co-downregulation of a program highly expressed in human MLL-AML (this study) and murine MLL-leukemia (Krivtsov et al. 2006) stem cells including HOXA10, MEIS1, PBX3 and MEF2C. Our data indicates an important role for HOXA9 in human MLL-rearranged leukemias, and suggests targeting HOXA9 or downstream programs may be a novel therapeutic option. Experiment Overall Design: RNA was purified from t(9;11) MOLM-14 AML cells 44h after transduction in triplicates with 2 of the two most effective HOXA9shRNA constructs (3 x 1F3-HOXA9shRNA; 3 x 2A5-HOXA9shRNA) or GFP-controlshRNA (6x).
2009-01-26 | E-GEOD-13714 | biostudies-arrayexpress
Project description:HOXA9 and MEIS1 are essential downstream effectors of the MLL-AF9 oncoprotein during leukaemia induction. Leukaemia derived from MLL-AF9-transduced LSK cells has a more aggressive phenotype than that derived from HOXA9/MEIS1-transduced LSK cells. To determine differential gene expression that contributes to increased aggressiveness in MLL-AF9-induced leukaemia, microarray was performed on LSK cells transduced with MLL-AF9 versus HOXA/MEIS1 oncogenes.
2019-07-03 | E-MTAB-7355 | biostudies-arrayexpress
Project description:Meis1 is found cooperatively activated with Hoxa7/a9 in AML, and it indeed promotes leukemogenic activities of Hoxa9. It is important to identify downstream target genes of Meis1 to understand its cooperative activity with Hoxa9 in leukemogenesis. We used microarrays to detail the global programme of gene expression upon Meis1 knockout. Murine primary bone marrow cells of the Rosa26-Cre-ERT2 knock-in mouse were transformed by retroviral transduction of Hoxa9 and floxed Meis1. The immortalized bone marrow cells were treated with 2 μM of 4-hydroxytamoxifen to delete Meis1 cDNA. Gene expression profiles were compared between the original Hoxa9/Meis1-expressing cells and Meis1 deleted (Hoxa9 only) cells.
2015-01-01 | E-GEOD-50645 | biostudies-arrayexpress
Project description:HOXA9 and MEIS1 are essential downstream effectors of the MLL-AF9 oncoprotein during leukemia induction. Leukemia derived from MLL-AF9-transduced LSK cells has a more aggressive phenotype than that derived from HOXA9/MEIS1-transduced LSK cells. To determine differential miRNA expression that contributes to increased aggressiveness in MLL-AF9-induced leukemia, miRCURY LNA microRNA Array was performed on LSK cells transduced with MLL-AF9 versus HOXA/MEIS1 oncogenes.
2019-07-03 | E-MTAB-7356 | biostudies-arrayexpress
Project description:The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feed-forward loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, we show that Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
2017-06-14 | PXD004192 | Pride
Project description:Meis1 is found cooperatively activated with Hoxa7/a9 in AML, and it indeed promotes leukemogenic activities of Hoxa9. It is important to identify downstream target genes of Meis1 to understand its cooperative activity with Hoxa9 in leukemogenesis. We used microarrays to detail the global programme of gene expression upon Meis1 knockout.
2015-01-01 | GSE50645 | GEO
Project description:Analysis of gene expression profile of Hoxa9/Meis1 leukemia cells 6 days after loss of Jmjd1c. Loss of Jmjd1c induces differentiation and Hoxa9/Meis1 leukemia cells. These results provide insight into the role of Jmjd1c in AML with elelvated expression of Hoxa9.
2016-06-09 | GSE75580 | GEO
Project description:OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX proteins, such as HOXA9, to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. To further resolve these mechanisms, we conducted a structure-function analysis of Meis1 and miRNA expression profiling, in the context of Hoxa9 leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the homeodomain of Meis1 is required for leukemogenic collaboration with Hoxa9. miRNA expression profiling of a Hoxa9 preleukemic cell line transduced with wild-type or Meis1 homeodomain mutant reveal deregulation of multiple miRNA including a set not previously implicated as Meis1 targets.
2017-04-27 | GSE74566 | GEO
Project description:OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX proteins, such as HOXA9, to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. To further resolve these mechanisms, we conducted a structure-function analysis of Meis1 and gene expression profiling, in the context of Hoxa9 leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the homeodomain of Meis1 is required for leukemogenic collaboration with Hoxa9. Gene expression profiling of a Hoxa9 preleukemic cell line transduced with wild-type or Meis1 homeodomain mutant reveal deregulation of multiple genes including a set not previously implicated as Meis1 targets.
2016-09-01 | GSE75272 | GEO