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Principal Investigator: Daniel Lacorazza
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $426,306
Funding agency: National Cancer Institute
Project Summary
Chronic myeloid leukemia (CML) is an aggressive hematological malignancy caused by the oncoprotein
BCRABL1. Although tyrosine kinase inhibitors (TKIs) can help CML patients achieve molecular remission, they
cannot be fully cured because the leukemic stem cells (LSCs) are still present in the body. This application aims
to study a novel actionable mechanism that controls self-renewal and survival in LSCs with the intent to support
the early-stage development of LSC-specific frontline therapy that increases treatment-free remission upon TKI
discontinuation. Our team discovered that the transcription factor KLF4 represses the gene encoding the dual-
specificity tyrosine-phosphorylation regulated kinase DYRK2, allowing LSCs to self-renew and progress the
disease. Thus, deleting the Klf4 gene in a CML mouse model was associated with a lower frequency of LSCs,
leading to leukemia regression and DYRK2 protein upregulation. In addition, inhibiting the SIAH2 ubiquitin ligase
also leads to upregulating the DYRK2 protein, which is associated with cytotoxicity in CML cells. Based on these
findings, we hypothesize that DYRK2 is a critical checkpoint that inhibits the survival and self-renewal in LSCs
that can be activated through genetic and pharmacological stabilization of the DYRK2 protein. In this application,
we propose to investigate the regulation of DYRK2 in CML LSCs through genetic studies to validate this
molecular target and identify DYRK2 stabilizers for drug development. In Specific Aim 1, we propose to study
the mechanism of DYRK2 activation in LSC self-renewal through the phosphorylation of downstream targets. In
Specific Aim 2, we will explore the genetic stabilization of the DYRK2 protein by deleting the gene encoding the
ubiquitin ligase SIAH2 and performing a genome-wide CRISPR/Cas9 screen to identify pathways regulating
DYRK2 expression. In Specific Aim 3, we propose investigating the anti-leukemic properties of pharmacological
stabilization of DYRK2 protein with small molecules identified in a biased approach and cell-based screens in
pre-clinical mouse models as single agents or combined with imatinib. These comprehensive studies will
elucidate how DYRK2 regulates LSCs, how DYRK2 expression is regulated, and what small molecules stabilize
DYRK2 protein for developing LSC-directed therapy in leukemia.
Terms: <2-Methyl-1,4-naphthalenedione><2-Methyl-1,4-naphthoquinone><2-Methylnaphthoquinone><ABL1><ABL1 gene><Abelson Murine Leukemia Viral Oncogene Homolog 1><Address><Antioncogene Protein p53><Apoptosis><Apoptosis Pathway><Biology><Blood Precursor Cell><CD34><CD34 gene><CRISPR approach><CRISPR based approach><CRISPR editing screen><CRISPR method><CRISPR methodology><CRISPR screen><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based screen><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 screen><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Line><CellLine><Cells><Cellular Tumor Antigen P53><Chronic Granulocytic Leukemia><Chronic Myelocytic Leukemia><Chronic Myelogenous Leukemia><Chronic Myeloid Leukemia><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Dependence><Development><Disease><Disease remission><Disorder><Dose><Drugs><EZF protein><Frequencies><Future><GKLF protein><Gene Deletion><Gene Down-Regulation><Gene Transcription><Genes><Genetic><Genetic Transcription><Genetic study><Goals><HPCA1><Healthcare><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematology><Hematopoietic Cancer><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Progenitor Cells><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hematopoietic stem cells><High Throughput Assay><Human><Imatinib><JTK7><KO mice><Kinases><Klf4 protein><Knock-in><Knock-out Mice><Knockout Mice><Kruppel-like factor 4><Kruppel-like transcription factors><Laboratories><Leukemic progenitor and stem cell><Lytotoxicity><Malignant Hematologic Neoplasm><Malignant Hematopoietic Neoplasm><Mediating><Medical><Medication><Menadione><Mice><Mice Mammals><Modern Man><Molecular><Molecular Target><Murine><Mus><Null Mouse><Oncogene Products><Oncogene Proteins><Oncoprotein p53><Oncoproteins><P53><PDX model><PTK Inhibitors><Pathway interactions><Patient derived xenograft><Patients><Pharmaceutical Preparations><Pharmacological Study><Pharmacology Study><Phosphoprotein P53><Phosphoprotein pp53><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Play><Population><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Programmed Cell Death><Property><Protein Cleavage><Protein Phosphorylation><Protein TP53><Protein Tyrosine Kinase Inhibitors><Proteins><Proteolysis><Publishing><RNA Expression><Recurrent disease><Regulation><Relapsed Disease><Remission><Research><Role><Specificity><Strains Cell Lines><Survivors><TK Inhibitors><TP53><TP53 gene><TRP53><Testing><Therapeutic><Toxic effect><Toxicities><Transcription><Transcription Repression><Transcriptional Repression><Transphosphorylases><Tumor Protein p53><Tumor Protein p53 Gene><Tyrosine Kinase Inhibitor><Tyrosine Phosphorylation><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Up-Regulation><Upregulation><Vitamin K 3><Vitamin K3><blood cancer><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><c myc><c-Abl><c-abl Genes><c-abl Proto-Oncogenes><c-myc Genes><cancer of blood><cancer of the blood><cancer progenitor><cancer progenitor cells><cancer stem cell><check point inhibition><checkpoint inhibition><chemical library><chronic myelogenous leukemia cell><chronic myeloid leukemia cell><clinical translation><clinically translatable><clustered regularly interspaced short palindromic repeats screen><cmyc><cultured cell line><cytotoxic><cytotoxicity><developmental><drug development><drug/agent><effective therapy><effective treatment><epithelial zinc finger protein><gene deletion mutation><gene repression><genome scale><genome-wide><genomewide><gut-enriched Kruppel-like factor><health care><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><high throughput screening><immune check point inhibition><immune checkpoint inhibition><improved><in vivo monitoring><knockin><leukemia><leukemic progenitor><leukemic stem cell><leukemogenesis><malignant progenitor><malignant stem cell><mouse model><murine model><novel><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><patient derived xenograft model><pharmacologic><pre-clinical><preclinical><preservation><prevent><preventing><progenitor biology><progenitor cell biology><progenitor cell expansion><progenitor cell regeneration><progenitor cell self renewal><progenitor expansion><progenitor regeneration><progenitor self renewal><protein p53><relapse patients><self-renew><self-renewal><small molecule><small molecule libraries><social role><stem and progenitor biology><stem and progenitor cell expansion><stem and progenitor cell regeneration><stem and progenitor cell self renewal><stem cell biology><stem cell expansion><stem cell regeneration><stem cell self renewal><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><ubiquitin ligase><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog>