The LMO2-LDB1-TAL1 complex regulates transcription networks in AML [ChIP-Seq]
Relapsed acute myeloid leukemia (relAML) remains a clinical challenge. We have shown that epigenetic heterogeneity may contribute to transcriptional dysregulation and disease progression in AML, but the specific transcriptional programs have not been identified. To characterize relAML transcriptional landscapes, we analyzed molecular profiles from patient-matched diagnostic and relapse AML specimens. A subset of differentially expressed genes (DEGs) that were disparate in direction of expression change identified two patient subtypes, but were not associated with specific molecular events. We predicted transcriptional regulators (TRs) that might regulate the expression patterns observed. The expression patterns of the top TRs predicted for the disparate genes associated with clinical outcomes in independent AML patient cohorts. The top TRs predicted included members of the LMO2 multi-subunit complex (TAL1 and LDB1).  LMO2/LDB1/TAL1 complex members were also identified as potential TRs of DEGs in a patient derived xenograft mouse model of relapse.  Analysis of DepMap data identified LMO2-dependent cells with a subset highly expressing TAL1, suggesting coordinated regulation. TAL1 co-purified in immunoprecipitation for LMO2 and LDB1 followed by tandem mass spectrometry analysis in HEL and K562 cells. Loss of function experiments targeting LMO2/LDB1/TAL1 in AML cell lines associated with reduced cell growth, downregulation of cell cycle genes, and a negative association with gene expression patterns observed in relapsed patients with increased TAL1 expression. Data from primary AML specimens and functional analyses of AML cell lines supports an essential role for the LMO2/LDB1/TAL1 complex in relAML. Targeting the complex or downstream effectors could provide novel therapeutic considerations for relAML patients. Overall design: K562 cells were crosslinked and chromatin was isolated. 4 ug of LDB1 antibody was incubated for every 20 ug of chromatin. LDB1 incubated chromatin was compared to input samples.