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1.
Cancer Discov ; 12(12): 2880-2905, 2022 12 02.
Article in English | MEDLINE | ID: mdl-36305736

ABSTRACT

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell-like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. SIGNIFICANCE: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1-BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma. See related commentary by Beytagh and Weiss, p. 2730. See related article by Mo et al., p. 2906.


Subject(s)
Epigenome , Glioma , Animals , Humans , Mutation , Glioma/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Neoplastic Stem Cells/metabolism , Mammals/genetics , Mammals/metabolism , DNA Helicases/genetics , Nuclear Proteins/genetics
2.
JCI Insight ; 7(19)2022 10 10.
Article in English | MEDLINE | ID: mdl-36040810

ABSTRACT

Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter-methylated adult and pediatric gliomas and neuroblastomas.


Subject(s)
Glioma , Neuroblastoma , Vaccinia , Child , Glioma/genetics , Humans , Intracellular Signaling Peptides and Proteins , Nervous System , Neuroblastoma/genetics , Protein Serine-Threonine Kinases/genetics , Vaccinia virus
3.
Pediatrics ; 148(6)2021 12 01.
Article in English | MEDLINE | ID: mdl-34814185

ABSTRACT

Inflammatory myofibroblastic tumor (IMT) is a rare, mesenchymal tumor that has an increased incidence in childhood. Tumors are usually isolated to the chest, abdomen, and retroperitoneum, but metastatic presentations can be seen. Presenting symptoms are nonspecific and include fever, weight loss, pain, shortness of breath, and cough. Approximately 85% of IMTs harbor actionable kinase fusions. The diagnosis can be delayed because of overlapping features with inflammatory disorders, such as elevated inflammatory markers, increased immunoglobin G levels, fever, weight loss, and morphologic similarity with nonmalignant conditions. We present a girl aged 11 years with a TFG-ROS1 fusion-positive tumor of the lung that was initially diagnosed as an immunoglobin G4-related inflammatory pseudotumor. She underwent complete left-sided pneumonectomy and later recurred with widely metastatic disease. We then report the case of a boy aged 9 years with widely metastatic TFG-ROS1 fusion-positive IMT with rapid molecular diagnosis. In both children, there was an excellent response to oral targeted therapy. These cases reveal that rapid molecular testing of inflammatory tumors is not only important for diagnosis but also reveals therapeutic opportunities. Targeted inhibitors produce significant radiologic responses, enabling potentially curative treatment approaches for metastatic ROS1 fusion IMT with previously limited treatment options. Primary care pediatricians and pediatric subspecialists have a crucial role in the early consultation of a pediatric oncology center experienced in molecular diagnostics to facilitate a comprehensive evaluation for children with inflammatory tumors.


Subject(s)
Lung Neoplasms/genetics , Neoplasms, Muscle Tissue/genetics , Oncogene Proteins, Fusion/genetics , Protein-Tyrosine Kinases/genetics , Proteins/genetics , Proto-Oncogene Proteins/genetics , Antineoplastic Agents, Immunological/therapeutic use , Child , Crizotinib/therapeutic use , Diagnosis, Differential , Female , Glucocorticoids/therapeutic use , Humans , Immunoglobulin G4-Related Disease/diagnosis , Inflammation/diagnosis , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Lung Neoplasms/surgery , Male , Molecular Targeted Therapy/methods , Neoplasm Recurrence, Local , Neoplasms, Muscle Tissue/diagnosis , Neoplasms, Muscle Tissue/drug therapy , Neoplasms, Muscle Tissue/surgery , Pancreatic Neoplasms/secondary , Plasma Cell Granuloma, Pulmonary/diagnosis , Rare Diseases/diagnosis , Rare Diseases/drug therapy , Rare Diseases/genetics , Rare Diseases/surgery , Rituximab/therapeutic use
4.
Immunity ; 51(3): 479-490.e6, 2019 09 17.
Article in English | MEDLINE | ID: mdl-31402259

ABSTRACT

Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142-/- mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-ß (TGF-ß) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.


Subject(s)
Homeostasis/immunology , Immunity, Innate/immunology , Lymphocytes/immunology , MicroRNAs/immunology , Animals , Cell Line , Female , HEK293 Cells , Humans , Killer Cells, Natural/immunology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Muromegalovirus/immunology , NIH 3T3 Cells , Receptors, Interleukin-15/immunology , Signal Transduction/immunology , Suppressor of Cytokine Signaling Proteins/immunology , Transforming Growth Factor beta/immunology
5.
Cancer Res ; 78(13): 3510-3521, 2018 07 01.
Article in English | MEDLINE | ID: mdl-29724719

ABSTRACT

Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased ASH1L protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors. Mir142 loss also enhanced the disease-initiating activity of IDH2-mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing HOXA9/A10 expression during normal myeloid differentiation. AML-associated loss-of-function mutations of MIR142 disrupt this negative signaling pathway, resulting in sustained HOXA9/A10 expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.Significance: These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. Cancer Res; 78(13); 3510-21. ©2018 AACR.


Subject(s)
DNA-Binding Proteins/genetics , Gene Expression Regulation, Leukemic , Histone-Lysine N-Methyltransferase/genetics , Leukemia, Myeloid, Acute/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Transcription Factors/genetics , Animals , Bone Marrow/pathology , Carcinogenesis/genetics , DNA-Binding Proteins/metabolism , Disease Models, Animal , HEK293 Cells , Hematopoietic Stem Cells/pathology , Histone-Lysine N-Methyltransferase/metabolism , Homeobox A10 Proteins , Homeodomain Proteins/metabolism , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/pathology , Loss of Function Mutation , Mice , Mice, Inbred C57BL , Mice, Knockout , Point Mutation , Receptor, EphB2 , Signal Transduction/genetics , Transcription Factors/metabolism
6.
PLoS One ; 10(3): e0119304, 2015.
Article in English | MEDLINE | ID: mdl-25793640

ABSTRACT

MIR233 is genetically or epigenetically silenced in a subset of acute myeloid leukemia (AML). MIR223 is normally expressed throughout myeloid differentiation and highly expressed in hematopoietic stem cells (HSCs). However, the contribution of MIR223 loss to leukemic transformation and HSC function is largely unknown. Herein, we characterize HSC function and myeloid differentiation in Mir223 deficient mice. We show that Mir223 loss results in a modest expansion of myeloid progenitors, but is not sufficient to induce a myeloproliferative disorder. Loss of Mir223 had no discernible effect on HSC quiescence, long-term repopulating activity, or self-renewal capacity. These results suggest that MIR223 loss is likely not an initiating event in AML but may cooperate with other AML associated oncogenes to induce leukemogenesis.


Subject(s)
Cell Differentiation/genetics , Cell Self Renewal/genetics , Granulocytes/cytology , Granulocytes/metabolism , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Myelopoiesis/genetics , Animals , Cell Count , Female , Leukemia, Myeloid, Acute/genetics , Leukocyte Count , Male , Mice , Mice, Knockout , MicroRNAs , Neutrophils , Stress, Physiological
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