MLL3 Is a Haploinsufficient 7q Tumor Suppressor in Acute Myeloid Leukemia
Copyright policy )MLL3 Is a Haploinsufficient 7q Tumor Suppressor in Acute Myeloid Leukemia
Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease.
- University of California, San Francisco United States
- Department of Pediatric Oncology Dana-Farber Cancer Institute Harvard Medical School United States
- University of Chicago United States
- Dana-Farber Cancer Institute United States
- Cold Spring Harbor Laboratory United States
Myeloid, Cancer Research, Drug Resistance, Gene Dosage, Haploinsufficiency, Inbred C57BL, Cell Transformation, Mice, Clustered Regularly Interspaced Short Palindromic Repeats, RNA, Small Interfering, Cancer, Pediatric, Leukemia, Cell Differentiation, Hematology, Azepines, Biological Sciences, Leukemia, Myeloid, Acute, Cell Transformation, Neoplastic, Oncology, Pair 7, RNA Interference, Chromosome Deletion, Chromosomes, Human, Pair 7, Myeloid-Lymphoid Leukemia Protein, Human, Biotechnology, Childhood Leukemia, Pediatric Cancer, Oncology and Carcinogenesis, Acute, Small Interfering, Chromosomes, Rare Diseases, Genetics, Animals, Humans, Oncology & Carcinogenesis, Neoplastic, Biomedical and Clinical Sciences, Tumor Suppressor Proteins, Neurosciences, Oncology and carcinogenesis, Cell Biology, Histone-Lysine N-Methyltransferase, Triazoles, Stem Cell Research, Mice, Inbred C57BL, Drug Resistance, Neoplasm, Biochemistry and cell biology, RNA, Neoplasm
Myeloid, Cancer Research, Drug Resistance, Gene Dosage, Haploinsufficiency, Inbred C57BL, Cell Transformation, Mice, Clustered Regularly Interspaced Short Palindromic Repeats, RNA, Small Interfering, Cancer, Pediatric, Leukemia, Cell Differentiation, Hematology, Azepines, Biological Sciences, Leukemia, Myeloid, Acute, Cell Transformation, Neoplastic, Oncology, Pair 7, RNA Interference, Chromosome Deletion, Chromosomes, Human, Pair 7, Myeloid-Lymphoid Leukemia Protein, Human, Biotechnology, Childhood Leukemia, Pediatric Cancer, Oncology and Carcinogenesis, Acute, Small Interfering, Chromosomes, Rare Diseases, Genetics, Animals, Humans, Oncology & Carcinogenesis, Neoplastic, Biomedical and Clinical Sciences, Tumor Suppressor Proteins, Neurosciences, Oncology and carcinogenesis, Cell Biology, Histone-Lysine N-Methyltransferase, Triazoles, Stem Cell Research, Mice, Inbred C57BL, Drug Resistance, Neoplasm, Biochemistry and cell biology, RNA, Neoplasm
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