Using a wide array of histological and electrophysiological

Using a wide array of histological and electrophysiological experimental approaches, these data clearly support a mechanistic role of neuronal nadph oxidase in the intrinsic epileptogenicity of human HH and strenghten the cellular model in which HH neuron clusters of spontaneously firing interneurons paradoxically excite projection neurons in a functional network (). Although the increase in Cx36 may be due to the developmental phenotype of HH neurons, the study suggests relevant insights on future therapeutic strategies, i.e. the use of gap-junction blockers such as carbenoxolone and tonabersat, to address the severely drug-refractory epileptic encephalopathy that affects patients.
In this issue, Burgermeister et al., present very interesting data on the function of DOK1, an enigmatic multifunctional adaptor protein (). Previous studies nicely summarized by the authors, have shown that DOK1 functions as a tumor suppressor by negatively regulating signaling via its interaction with p120 RAS GTPase-activating protein (GAP) to dampen MAPK signaling cascades downstream of receptor and non-receptor kinases in various cellular contexts (). Remarkably, knockout studies demonstrated hematopoietic defects () and development of sarcomas with the loss of other DOK members (). The studies of DOK1 function were not only complicated by the presence of several protein isoforms encoded by the same DOK1, but also dynamic shifts of the protein between the nucleus and the cytosol in resting and proliferating cells, respectively. Regarding the docking of DOK1, the full-length p62 DOK1 has an N-terminal plextrin homology (PH) domain for membrane binding, and a phospho-tyrosine-binding (PTB) domain thought to be involved in interactions with other protein partners. Unexpectedly, the authors convincingly demonstrate that the C-terminal PTB domain has yet another partner which directly regulates cell growth. And this is when peroxisome proliferator-activated receptor gamma (PPARg) enters the stage. Detailed experiments demonstrate not only the physical interactions between the two novel partners, but also a sensitivity of common cancer cell lines to PPARg agonists in a DOK1-dependent manner. The potential for repurposing of PPARg agonists, an established class of anti-diabetic medications, is one of the practical implications of the results of the Burgermeister et al. paper. As for the clinical relevance, the authors demonstrate that the loss of DOK1 expression portends worse survival in patients with colorectal cancer.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While most children with ALL are cured, the prognosis in adolescence and young adults (AYA) as well as older individuals is worse. The deleterious effects of age on prognosis are partially explained by the decrease of the good prognosis initiating chromosomal aberrations ( fusions and hyperdiploidy) and an increase of bad prognosis subtypes ( and translocations). Yet as most of the genomic studies were done on childhood ALL, relatively little is known on AYA and adult ALL. Especially less is known on the genomic characteristics of the “B-others” subgroup – the heterogeneous subgroup of ALLs lacking the known chromosomal translocations. The paper by Liu et al. from the Shanghai Institute of Hematology () markedly fills this void of knowledge. They performed DNA sequencing of close to 400 children and adults diagnostic and remission samples of ALL, identifying 325 recurrent somatic non-synonymous mutations in protein coding genes, a third of which were never reported before. In addition they performed RNA sequencing of 78 adults and 94 children and identified 29 new in-frame fusions. Adult ALLs were characterized with more mutations especially in epigenetic and B cell developmental genes and, as previously reported, by more “B others” ALLs. Yet, reflecting probably the different ethnic origins the frequency of “Philadelphia like” “CRLF2 fusions” ALLs (reviewed in ()) seems to be lower in the Asian patients.