ENAapplication/xmlftp.sra.ebi.ac.uk/vol1/fastq/SRR548/009/SRR5488489/SRR5488489.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/000/SRR5488480/SRR5488480.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/006/SRR5488476/SRR5488476.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/007/SRR5488487/SRR5488487.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/008/SRR5488478/SRR5488478.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/002/SRR5488482/SRR5488482.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/004/SRR5488474/SRR5488474.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/003/SRR5488493/SRR5488493.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/004/SRR5488484/SRR5488484.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/005/SRR5488495/SRR5488495.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/000/SRR5488490/SRR5488490.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/003/SRR5488473/SRR5488473.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/005/SRR5488475/SRR5488475.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/004/SRR5488494/SRR5488494.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/002/SRR5488492/SRR5488492.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/001/SRR5488481/SRR5488481.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/009/SRR5488479/SRR5488479.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/006/SRR5488486/SRR5488486.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/006/SRR5488496/SRR5488496.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/005/SRR5488485/SRR5488485.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/003/SRR5488483/SRR5488483.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/008/SRR5488488/SRR5488488.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/007/SRR5488477/SRR5488477.fastq.gzftp.sra.ebi.ac.uk/vol1/fastq/SRR548/001/SRR5488491/SRR5488491.fastq.gzprimaryOK200GenomicsStanford, Ottawa Hospital Research Institutehttps://www.ebi.ac.uk/ena/browser/view/PRJNA384956Homo sapiensDeep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that Metal Response Element Binding Transcription Factor 2/Polycomblike 2 (MTF2/PCL2) plays a fundamental role in the Polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2-PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2- deficient CD34+CD38- cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft (PDX) mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML. Overall design: Fold change analysis between treatment and controlENAMyelocytic, leukemia, acute myeloblastic leukemia, acute myelocytic leukemia, HDMX, acute Nonlymphocytic leukemia, acute myelogenous leukemia, acute myeloid leukemia not otherwise categorized, second cervical vertebra, acute non lymphoblastic leukemia, acute myeloid leukaemia NOS, ACTFS, axis, acute myeloblastic leukaemia, C76717, acute myelogenous leukaemia, acute myeloid leukemia not otherwise specified, TDRD19A, stalk, C2 vertebra, somatic, acute myelogenous leukemias, autosomal dominant, 9230112N11Rik, AML, axis vertebra, cervical axis, acute granulocytic leukemia, acute non lymphoblastic leukaemia, M96, 1700007J15Rik, acute myeloid leukemia NOS, NOS, acute myeloid, unclassified acute myeloid leukemia, M4/M4Eo subtype, Pcl2, PCL2, myeloid leukemia, acute myeloid leukaemia (AML), acute, acute myeloid leukaemia not otherwise categorised, unclassified AML, hematopoeitic - acute Myleogenous leukaemia (AML), Leukemia, cervical vertebra 2, C2, susceptibility to, hdm2, axis (CII), NAM1, AA415488, acute myeloid leukemia, acute myeloid leukaemia, Mdm-2, acute granulocytic leukaemia, axis [C II], acute myelocytic leukaemia, AML - acute myeloid leukemia, culm, RGD1304727, hematopoeitic - acute Myleogenous leukemia (AML), dJ976O13.2, AA537621, unclassified acute myeloid leukaemia, vertebra 2, acute myeloid leukemia (AML), acute Nonlymphocytic leukaemia, reduced survival in, AML - acute myeloid leukaemia, acute nonlymphocytic leukemia, ANLL, myelocytic, MDM2, Chemotherapy., acute nonlymphocytic leukaemia, acute myeloid leukaemia not otherwise specified, somatic mutation, AML - acute Myeloid Leukemia, acute myelogenoushuman being, human., man0.00.00.00.00.0falseHomo sapiensTargeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy [ChIP-Seq]2022-05-122018-08-02PRJNA384956GSE983789606