The LMO2-LDB1-TAL1 complex regulates transcription networks in acute myeloid leukemia
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 (DEG) that were disparate in direction of expression change identified 2 patient subtypes. We predicted that transcriptional regulators (TR) might regulate the expression patterns observed. The expression patterns of the top TR predicted for the disparate genes associated with clinical outcomes. The top TR predicted for the disparate DEG and DEG identified in a patient-derived xenograft model of relAML included members of the LIM domain only 2 - LIM domain binding 1 - TAL BHLH TF1, erythroid differentiation factor (LMO2-LDB1-TAL1) multisubunit complex (LTMC). Analysis of DepMap data identified LMO2-dependent cells with a subset highly expressing TAL1, suggesting coordinated regulation. TAL1 copurified 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 patients with AML.
Authors
- Richard Dillon (ORCID: https://orcid.org/0000-0001-9333-5296)
- Cem Meydan (ORCID: https://orcid.org/0000-0002-0663-6216)
- Donna Neuberg (ORCID: https://orcid.org/0000-0003-2566-3145)
- Chongzhi Zang (ORCID: https://orcid.org/0000-0003-4812-3627)
- Ari Melnick (ORCID: https://orcid.org/0000-0002-8074-2287)
- W. Hayes McDonald (ORCID: https://orcid.org/0000-0002-3510-426X)
- B. Bishal Paudel (ORCID: https://orcid.org/0000-0002-5426-7048)
- Ross L. Levine (ORCID: https://orcid.org/0000-0002-7884-1905)
- Paul Zumbo (ORCID: https://orcid.org/0000-0001-7234-2024)
- Martin Carroll (ORCID: https://orcid.org/0000-0002-5622-3735)
- Zhenjia Wang (ORCID: https://orcid.org/0000-0001-5576-0689)
- Richard J. D’Andrea (ORCID: https://orcid.org/0000-0002-4915-4612)
- Lars Bullinger (ORCID: https://orcid.org/0000-0002-5890-5510)
- Bernhard Maier (ORCID: https://orcid.org/0000-0002-8174-0873)
- Caroline Sheridan (ORCID: https://orcid.org/0000-0003-4621-7507)
- Stefan Bekiranov (ORCID: https://orcid.org/0000-0002-3177-4346)
- Utpal P. Davé (ORCID: https://orcid.org/0000-0002-9416-1686)
- Joyce Hardwick
- Yaseswini Neelamraju (ORCID: https://orcid.org/0000-0001-5840-652X)
- Yan Guo (ORCID: https://orcid.org/0000-0002-7364-2392)
- Subhash Prajapati (ORCID: https://orcid.org/0000-0002-2551-3895)
- Gloria Sheynkman (ORCID: https://orcid.org/0000-0002-4223-9947)
- Franck Rapaport (ORCID: https://orcid.org/0000-0001-6553-2110)
- Hao Fan (ORCID: https://orcid.org/0000-0002-9281-8760)
- Nicholas Dunham (ORCID: https://orcid.org/0000-0001-8995-3892)
- Justin H. Layer
- Francine E. Garrett-Bakelman (ORCID: https://orcid.org/0000-0002-4771-628X)
- Christopher E. Mason (ORCID: https://orcid.org/0000-0002-1850-1642)
- Michael W. Becker (ORCID: https://orcid.org/0000-0001-9890-8815)
- TH Lee (ORCID: https://orcid.org/0000-0002-7554-4059)
- Jorge Gandara (ORCID: https://orcid.org/0000-0002-7720-9676)
- Fady Abdelmalak
- Isaani Patnaik
Institutions
- South Australia Pathology (AU)
- Indiana University Health (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Miami (US)
- University of South Australia (AU)
- King's College London (GB)
- Vanderbilt University (US)
- Cornell University (US)
- Richard L. Roudebush VA Medical Center (US)
- Dana-Farber Cancer Institute (US)
- University of Virginia Medical Center (US)
- Centre for Cancer Biology (AU)
- University Hospital Ulm (DE)
- Weill Cornell Medicine (US)
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center
- University of Virginia Cancer Center
- Indiana University School of Medicine
- University of Virginia (US)
- University of Rochester (US)
- Indiana University – Purdue University Indianapolis (US)
- Charité - Universitätsmedizin Berlin (DE)
- University of Pennsylvania (US)
Publication Details
- Journal
- Blood Neoplasia
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1016/j.bneo.2025.100186
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00