TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in DNA1,2. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies3. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukemia (CMML), acute myeloid leukemias (AML) and secondary AML (sAML)4–12. We show here that TET2 mutations associated with myeloid malignancies compromise TET2 catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5-hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5-hmC versus healthy controls, but samples from patients with low 5-hmC showed hypomethylation relative to controls at the majority of differentially-methylated CpG sites. Our results demonstrate that TET2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5-hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anti-cancer drugs.

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Although aplastic anemia and myelodysplasia have been extensively investigated, little is known about their circulating cytokine patterns. We compared plasma soluble cytokines in 33 aplastic anemia, 57 myelodysplasia patients, and 48 healthy controls. High levels of thrombopoietin and granulocyte colony-stimulating factor, with low levels of CD40 ligand, chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 11, epidermal growth factor, vascular endothelial growth factor, and chemokine (C-C motif) ligand 11 were a signature profile for aplastic anemia. High levels of tumor necrosis factor-α, interleukin-6, chemokine (C-C motif) ligand 3, interleukin-1 receptor antagonist, and hepatocyte growth factor were a cytokine signature for myelodysplasia. Despite similar clinical presentations, distinct cytokine profiles were observed between aplastic anemia and hypocellular myelodysplasia. Future studies focusing on cytokines that better discriminate these two entities such as thrombopoietin and chemokine (C-C motif) ligand 3 may be useful tools in clinical practice.

Women represent approximately half of students entering medical schools and more than half of those entering PhD programs. When advancing through the academic and professional fields, however, women continually face barriers that men do not. In this Commentary, the authors offer ideas for coordinating the efforts of organizations, academic institutions, and leaders throughout the scientific and medical professions to reduce barriers that result in inequities and, instead, strive for gender parity. Specific areas of focus outlined by the authors include facilitating women’s access to formal and informal professional networks, acknowledging and addressing the gender pay gap as well as the lack of research funding awarded to women in the field, and updating workplace policies that have not evolved to accommodate women’s lifestyles. As academic institutions seek access to top talent and the means to develop those individuals capable of generating the change medicine and science needs, the authors urge leaders and change agents within academic medicine to address the systemic barriers to gender equity that impede us from achieving the mission to improve the health of all.

Mitochondrial complex V (CV) generates cellular energy as adenosine triphosphate (ATP). Mitochondrial disease caused by the m.8993T>G pathogenic variant in the CV subunit gene MT-ATP6 was among the first described human mitochondrial DNA diseases. Due to a lack of clinically available functional assays, validating the definitive pathogenicity of additional MT-ATP6 variants remains challenging. We reviewed all reported MT-ATP6 disease cases (n = 218) to date, to assess for MT-ATP6 variants, heteroplasmy levels, and inheritance correlation with clinical presentation and biochemical findings. We further describe the clinical and biochemical features of a new cohort of 14 kindreds with MT-ATP6 variants of uncertain significance. Despite extensive overlap in the heteroplasmy levels of MT-ATP6 variant carriers with and without a wide range of clinical symptoms, previously reported symptomatic subjects had significantly higher heteroplasmy load (p = 2.2 x 10 -16 ). Pathogenic MT-ATP6 variants resulted in diverse biochemical features. The most common findings were reduced ATP synthesis rate, preserved ATP hydrolysis capacity, and abnormally increased mitochondrial membrane potential. However, no single biochemical feature was universally observed. Extensive heterogeneity exists among both clinical and biochemical features of distinct MT-ATP6 variants. Improved mechanistic understanding and development of consistent biochemical diagnostic analyses are needed to permit accurate pathogenicity assessment of variants of uncertain significance in MT-ATP6.

While more women are in leadership positions in academic medicine now than ever before in U.S. history, evidence from recent surveys of women and graduating medical students demonstrates that sexual harassment continues in academic health centers. Academic medicine's ability to change its culture is hampered by victims' fear of reporting episodes of harassment, which is largely due to fear of retaliation. In this Perspective, the authors describe efforts in scientific societies to address the issue of sexual harassment and to begin to establish safe environments at national meetings. The authors contend that each institution must work to make it safe for individuals to come forward, to provide training for victims and for bystanders, and to abolish "locker room" talk that is demeaning to women.

The neurodiagnostic criteria of Leigh syndrome have not yet been clearly redefined based on the expanding of molecular etiologies. We aimed to analyze 20 years of clinical, genetic, and magnetic resonance studies from our Leigh syndrome cohort to provide a detailed description of central nervous system lesions in Leigh syndrome and their biological evolution in view of their genetic and clinical findings. Our study adds new neurodiagnostic insights to the current knowledge of Leigh syndrome, including association with overlapping syndromes, and the correlation of pathogenic genetic variants with neuroimaging phenotypes. ANN NEUROL 2020;88:218–232.

Mitochondrial short-chain enoyl-CoA hydratase deficiency (ECHS1D) is caused by mutations in ECHS1 (OMIM 602292) and is a recently identified inborn error of valine and fatty acid metabolism. This defect leads to secondary mitochondrial dysfunction. The majority of previously reported patients had the Leigh syndrome, with a median life expectancy of approximately 2 years. We report two siblings born 3 years apart with prenatal findings including facial dysmorphia, oligohydramnios, intrauterine growth restriction, and premature delivery. They had severe lactic acidosis with onset within the first hours of life, had congenital dilated cardiomyopathy, and died at 16 h of life and 2 days of life, respectively.Biochemical evaluation of these patients showed elevated butyryl-carnitine in the blood and elevated methylmalonyl/succinyl-CoA and decreased hydroxybutyryl-CoA in frozen liver of patient 2, confirming abnormal short-chain fatty acid metabolism. Elevated butyryl-carnitine has been reported only in a single previous case of ECHS1 deficiency, which also had neonatal onset. Pyruvate and lactate levels were both elevated with a normal pyruvate-lactate ratio. This supports the previous hypothesis that lactic acidosis in these patients results from secondary inhibition of the pyruvate dehydrogenase complex. The biomarker 2,3-dihydroxy-2-methylbutyric acid was detected in patient 2, but at lower levels than in previously reported cases.These cases extend our understanding of the severe end of the phenotypic spectrum of ECHS1 deficiency, clarify the range of biochemical abnormalities associated with this new disorder, and highlight the need to suspect this disease in patients presenting with comparable metabolic derangements and dysmorphic features.