DLK1 is a GATA1s-driven dependency and therapeutic target in Down syndrome–associated myeloid leukemia

作者：Lonneke Verboon, Sonali P. Barwe, Meredith Tavenner, Joshua R Faust, Hasan Issa, José Goncalves-Dias, K Schuschel, R Bhayadia, Patrick H. van Berkel, Aimy Sebastian, Rhonda E. Ries, Sophie Paczesny, Soheil Meshinchi, Johann Hitzler, Yana Pikman, E Anders Kolb, Dirk Heckl, Jan-Henning Klusmann, Anilkumar Gopalakrishnapillai · 发表于：Blood Advances · 年份：2026 · DOI：10.1182/bloodadvances.2025018830 · 被引用次数：1 · 研究领域：Acute Myeloid Leukemia Research、Chromatin Remodeling and Cancer、Zebrafish Biomedical Research Applications

ABSTRACT: Children with Down syndrome have a markedly increased risk of developing myeloid leukemia. Although having an excellent prognosis, 10% to 20% develop relapsed or refractory disease with poor survival, highlighting the need for new targeted approaches. The pathogenesis of myeloid leukemia of Down syndrome (ML-DS) is tightly linked to fetal hematopoiesis and mutations in GATA1, generating the truncated GATA1 short (GATA1s) isoform. We identified Delta-like noncanonical Notch ligand 1 (DLK1) as a direct GATA1s target. DLK1, a paternally imprinted transmembrane protein, is highly expressed in fetal liver CD34+ cells but absent in adult hematopoiesis, making it an attractive immunotherapeutic target. Chromatin profiling revealed GATA1s occupancy at a distal enhancer within the DLK1-DIO3 locus, driving aberrant DLK1 upregulation in ML-DS. Functional studies demonstrated that DLK1 is a leukemia dependency, as its genetic ablation impaired proliferation and engraftment, induced apoptosis, and altered Notch and β-catenin signaling. Therapeutically, a DLK1-directed antibody-drug conjugate-induced selective cytotoxicity, abrogated colony formation, and significantly prolonged survival in refractory ML-DS patient-derived xenograft (PDX) models, achieving durable remissions at higher doses. These findings establish DLK1 as a leukemia-specific vulnerability and provide preclinical proof-of-concept for DLK1-targeted therapies in ML-DS and other leukemias with fetal-like expression...