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RUNX1 isoform disequilibrium promotes the development of trisomy 21-associated myeloid leukemia.
Gialesaki, Sofia; Bräuer-Hartmann, Daniela; Issa, Hasan; Bhayadia, Raj; Alejo-Valle, Oriol; Verboon, Lonneke; Schmell, Anna-Lena; Laszig, Stephanie; Regényi, Eniko; Schuschel, Konstantin; Labuhn, Maurice; Ng, Michelle; Winkler, Robert; Ihling, Christian; Sinz, Andrea; Glaß, Markus; Hüttelmaier, Stefan; Matzk, Sören; Schmid, Lena; Strüwe, Farina Josepha; Kadel, Sofie-Katrin; Reinhardt, Dirk; Yaspo, Marie-Laure; Heckl, Dirk; Klusmann, Jan-Henning.
Afiliação
  • Gialesaki S; Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
  • Bräuer-Hartmann D; Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • Issa H; Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Bhayadia R; Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Alejo-Valle O; Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • Verboon L; Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Schmell AL; Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Laszig S; Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Regényi E; Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • Schuschel K; Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • Labuhn M; Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Ng M; Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
  • Winkler R; Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • Ihling C; Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Sinz A; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • Glaß M; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • Hüttelmaier S; Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • Matzk S; Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany.
  • Schmid L; Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • Strüwe FJ; Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
  • Kadel SK; Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
  • Reinhardt D; Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
  • Yaspo ML; Pediatric Hematology and Oncology, Pediatrics III, University Hospital Essen, Essen, Germany.
  • Heckl D; Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • Klusmann JH; Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Blood ; 141(10): 1105-1118, 2023 03 09.
Article em En | MEDLINE | ID: mdl-36493345
Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR-CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide / Síndrome de Down / Subunidade alfa 2 de Fator de Ligação ao Core Tipo de estudo: Risk_factors_studies Limite: Animals / Child / Humans Idioma: En Revista: Blood Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide / Síndrome de Down / Subunidade alfa 2 de Fator de Ligação ao Core Tipo de estudo: Risk_factors_studies Limite: Animals / Child / Humans Idioma: En Revista: Blood Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha