ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.

Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries.

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear.

Mechanisms of Leukemia Evolution: Lessons from a Congenital Syndrome.

Studies of the mechanisms of acute leukemia transformation from a preleukemic state in humans are hampered by the absence of clinical preleukemia syndromes. In this issue of Cancer Cell, Labuhn et al. provide a functional genomics view on the leukemic evolution from congenital preleukemia in children with Down syndrome.

Ser289 phosphorylation activates both DAPK1 and DAPK2 but in response to different intracellular signaling pathways.

DAPK1 and DAPK2 are calmodulin (CaM)-regulated protein kinases that share a high degree of homology in their catalytic and CaM regulatory domains. Both kinases function as tumor suppressors, and both have been implicated in autophagy regulation. Over the years, common regulatory mechanisms for the two kinases as well as kinase-specific ones have been identified.

Non-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy.

Autophagy is an intracellular degradation process essential for adaptation to metabolic stress. DAPK2 is a calmodulin-regulated protein kinase, which has been implicated in autophagy regulation, though the mechanism is unclear. Here, we show that the central metabolic sensor, AMPK, phosphorylates DAPK2 at a critical site in the protein structure, between the catalytic and the calmodulin-binding domains.

A model-driven methodology for exploring complex disease comorbidities applied to autism spectrum disorder and inflammatory bowel disease.

We propose a model-driven methodology aimed to shed light on complex disorders. Our approach enables exploring shared etiologies of comorbid diseases at the molecular pathway level. The method, Comparative Comorbidities Simulation (CCS), uses stochastic Petri net simulation for examining the phenotypic effects of perturbation of a network known to be involved in comorbidities to predict new roles for mutations in comorbid conditions.

Discovering protein-protein interactions within the programmed cell death network using a protein-fragment complementation screen.

Apoptosis and autophagy are distinct biological processes, each driven by a different set of protein-protein interactions, with significant crosstalk via direct interactions among apoptotic and autophagic proteins. To measure the global profile of these interactions, we adapted the Gaussia luciferase protein-fragment complementation assay (GLuc PCA), which monitors binding between proteins fused to complementary fragments of a luciferase reporter. A library encompassing 63 apoptotic and autophagic proteins was constructed for the analysis of ∼3,600 protein-pair combinations.

The DAPK family: a structure-function analysis.

DAP-kinase (DAPK) is the founding member of a family of highly related, death associated Ser/Thr kinases that belongs to the calmodulin (CaM)-regulated kinase superfamily. The family includes DRP-1 and ZIP-kinase (ZIPK), both of which share significant homology within the common N-terminal kinase domain, but differ in their extra-catalytic domains. Both DAPK and DRP-1 possess a conserved CaM autoregulatory domain, and are regulated by calcium-activated CaM and by an inhibitory auto-phosphorylation within the domain.