| Title: |
Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia |
| Authors: |
Tremblay, CS; Saw, J; Yan, F; Boyle, JA; Amarasinghe, O; Abdollahi, S; Vo, ANQ; Shields, BJ; Mayoh, C; McCalmont, H; Evans, K; Steiner, A; Parsons, K; McCormack, MP; Powell, DR; Wong, NC; Jane, SM; Lock, RB; Curtis, DJ |
| Source: |
urn:ISSN:0887-6924 ; urn:ISSN:1476-5551 ; Leukemia, 39, 3, 577-589 |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2025 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
32 Biomedical and Clinical Sciences; 3201 Cardiovascular Medicine and Haematology; Pediatric Cancer; Hematology; Stem Cell Research; Human Genome; Genetics; Stem Cell Research - Nonembryonic - Human; Childhood Leukemia; Regenerative Medicine; Biotechnology; Pediatric Research Initiative; Cancer; Cancer Genomics; Rare Diseases; Stem Cell Research - Nonembryonic - Non-Human; 2.1 Biological and endogenous factors; Animals; Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Drug Resistance; Neoplasm; Mice; LIM Domain Proteins; fms-Like Tyrosine Kinase 3; Adaptor Proteins; Signal Transducing; Transgenic; Signal Transduction; Proto-Oncogene Proteins |
| Description: |
Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is an immature subtype of T-cell acute lymphoblastic leukemia (T-ALL) commonly show deregulation of the LMO2-LYL1 stem cell transcription factors, activating mutations of cytokine receptor signaling, and poor early response to intensive chemotherapy. Previously, studies of the Lmo2 transgenic mouse model of ETP-ALL identified a population of stem-like T-cell progenitors with long-term self-renewal capacity and intrinsic chemotherapy resistance linked to cellular quiescence. Here, analyses of Lmo2 transgenic mice, patient-derived xenografts, and single-cell RNA-sequencing data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells expressing high levels of the cytokine receptor FLT3. Despite a highly proliferative state, these FLT3-overexpressing cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. Chromatin immunoprecipitation and assay for transposase-accessible chromatin sequencing demonstrated FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex. Media conditioned by Lmo2 transgenic thymocytes revealed an autocrine FLT3-dependent signaling loop that could be targeted by the FLT3 inhibitor gilteritinib. Consequently, gilteritinib impaired in vivo growth of ETP-ALL and improved the sensitivity to chemotherapy. Furthermore, gilteritinib enhanced response to the BCL2 inhibitor venetoclax, which may enable “chemo-free” treatment of ETP-ALL. Together, these data provide a cellular and molecular explanation for enhanced cytokine signaling in LMO2-driven ETP-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL. (Figure presented.) |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
http://purl.org/au-research/grants/nhmrc/APP1157871; https://hdl.handle.net/1959.4/103945 |
| DOI: |
10.1038/s41375-024-02491-5 |
| Availability: |
https://hdl.handle.net/1959.4/103945; https://doi.org/10.1038/s41375-024-02491-5 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.8B51E549 |
| Database: |
BASE |