Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML
Laura Barreyro,
Avery M. Sampson,
Kathleen Hueneman,
Kwangmin Choi,
Susanne Christie,
Vighnesh Ramesh,
Michael Wyder,
Dehua Wang,
Mario Pujato,
Kenneth D. Greis,
Gang Huang,
Daniel T. Starczynowski
Affiliations
Laura Barreyro
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Avery M. Sampson
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Kathleen Hueneman
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Kwangmin Choi
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Susanne Christie
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Vighnesh Ramesh
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Michael Wyder
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA
Dehua Wang
Department of Pathology & Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA; Department of Pathology, Cincinnati Children’s Hospital, Cincinnati, OH, USA
Mario Pujato
Life Sciences Computational Services, LLC, Huntingdon Valley, PA, USA
Kenneth D. Greis
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA
Gang Huang
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA; Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, TX, USA; Department of Pathology & Laboratory Medicine, UT Health San Antonio, San Antonio, TX, USA
Daniel T. Starczynowski
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA; University of Cincinnati Cancer Center, Cincinnati, OH, USA; Corresponding author
Summary: Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO hematopoietic stem and/or progenitor cells (HSPCs) expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.
