1. Relapsed AML patients have distinct transcriptomes potentially regulated by a core group of transcriptional co-regulators (LMO2-LDB1-TAL1).

  2. These transcriptional co-regulators can regulate cell cycle, proliferation, and potentially response to chemotherapeutic agents in patients.

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 aberrant transcriptional programs have not been identified. 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. We predicted that transcriptional regulators (TRs) might regulate the expression patterns observed. The expression patterns of the top TRs predicted for the disparate genes associated with clinical outcomes. The top TRs predicted for the disparate DEGs and DEGs identified in a patient derived xenograft model of relapsed AML included members of the LMO2 multi-subunit complex (TAL1 and LDB1; LTMC). 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, and results from chromatin immunoprecipitation experiments suggest significant co-occupancy of TAL1 and LDB1. Loss of function experiments targeting LMO2, LDB1, and 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. Our results from primary AML specimens and functional analyses of AML cell lines supports an essential role for the LTMC in AML. Targeting the complex or downstream effectors could provide novel therapeutic considerations for a subset of AML patients.

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Author notes

∗

Authors contributed equally

#

Authors contributed equally

© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
2025

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First page of The LMO2-LDB1-TAL1 complex regulates transcription networks in Acute Myeloid Leukemia

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