JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis
Authors: Lynch, Jennifer R.; Salik, Basit; Connerty, Patrick; Vick, Binje; Leung, Halina; Pijning, Aster; Jeremias, Irmela; Spiekermann, Karsten; Trahair, Toby; Liu, Tao; Haber, Michelle; Norris, Murray D.; Woo, Andrew J.; Hogg, Philip; Wang, Jianlong; Wang, Jenny Y.
Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem/progenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line-and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically.
Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
GENETICS IN MEDICINE
Authors: Saez, Mauricio A.; Fernandez-Rodriguez, Juana; Moutinho, Catia; Sanchez-Mut, Jose V.; Gomez, Antonio; Vidal, Enrique; Petazzi, Paolo; Szczesna, Karolina; Lopez-Serra, Paula; Lucariello, Mario; Lorden, Patricia; Delgado-Morales, Raul; de la Caridad, Olga J.; Huertas, Dori; Gelpi, Josep L.; Orozco, Modesto; Lopez-Doriga, Adriana; Mila, Montserrat; Perez-Jurado, Luis A.; Pineda, Mercedes; Armstrong, Judith; Lazaro, Conxi; Esteller, Manel
Purpose: Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders. Methods: We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect. Results: We found seven JMJD1C variants that were not present in any control sample (similar to 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity. Conclusions: Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.