Pharmacologic Inhibition of DYRK1A Results in MYC Hyperactivation and ERK Hyperphosphorylation rendering KMT2A -R ALL Cells Sensitive to BCL2 Inhibition
Year: 2022
Type: preprint
Abstract: KMT2A -rearranged ( KMT2A -R) B cell acute lymphoblastic leukemia (ALL) is a high-risk disease in children and adults that is often chemotherapy resistant. To identify non-cytotoxic approaches to therapy, we performed a domain-specific kinome-wide CRISPR screen in KMT2A -R cell lines and patient derived xenograft samples (PDX) and identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a potential target. Pharmacologic inhibition of the KMT2A-fusion transcriptional co-regulator Menin released the KMT2A-fusion complex from the DYRK1A promoter thereby lowering DYRK1A expression levels confirming DYRK1A as a direct target of the KMT2A fusion oncogene. Direct pharmacologic inhibition of DYRK1A decreased cell proliferation of KMT2A -R ALL, thereby confirming the requirement of DYRK1A in this ALL subtype. To further understand the biologic function of DYRK1A in KMT2A -R ALL, we leveraged pharmacologic DYRK1A inhibitors in KMT2A -R PDX and cell line models. DYRK1A inhibition consistently led to upregulation of MYC protein levels, and hyperphosphorylation of ERK, which we confirmed via in vivo treatment experiments. Furthermore, DYRK1A inhibition decreased ALL burden in mice. Our results further demonstrate that DYRK1A inhibition induces the proapoptotic factor BIM, but ERK hyperphosphorylation is the driving event that induces cell cycle arrest. In contrast, combined treatment of KMT2A -R ALL cells in vitro and in vivo with DYRK1A inhibitors and the BCL2 inhibitor, venetoclax, synergistically decreases cell survival and reduced the leukemic burden in mice. Taken together these results demonstrate a unique function of DYRK1A specially in KMT2A -R ALL. Synergistic inhibition of DRYK1A and BCL2 may provide a low-toxic approach to treat this high risk ALL subtype.
Authors: Christian Hurtz, V. S. S. Abhinav Ayyadevara, Gerald Wertheim, John A Chukinas, Joseph P Loftus, Sung June Lee, Anil Kumar, Rahul S Bhansali, Srividya Swaminathan, Huimin Geng, Thomas Milne, Xianxin Hua, Kathrin M Bernt, Thierry Besson, Junwei Shi, John D. Crispino, Martin Carroll, Sarah K Tasian
Institutions: Temple University, University of Pennsylvania, Children's Hospital of Philadelphia, City of Hope, Beckman Research Institute, City Of Hope National Medical Center, University of California, San Francisco, University of Oxford, MRC Weatherall Institute of Molecular Medicine, Abramson Cancer Center, Centre National de la Recherche Scientifique, Laboratoire COBRA, Université de Rouen Normandie
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, American Society of Hematology, Rally Foundation, Leukemia and Lymphoma Society, Children's Hospital of Philadelphia, University of Pennsylvania, Andrew McDonough B+ Foundation, National Institutes of Health, University of California, Irvine, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W4301366129