Transcriptional analysis of primary AML patient samples.

Supplementary Table S5 shows the rank order list of genes targeted by sgRNAs enriched in the custom minipool CRISPR/Cas9 knockout screens.

Inhibition of KDM5 enzymes by the (R)- and (S)-enantiomers of 2-hydroxyglutarate.

Characterization of isogenic TF-1 cell lines expressing TET2-targeting shRNAs.

Supplementary Table S1 shows the frequencies of TET2 and IDH mutations in clonal myeloid disorders.

Supplementary Table S7 shows the gene set enrichment analysis gene set that corresponds to Figure 4E.

Genomic regions marked by increased trimethyl-H3K4 are enriched in IDH1-mutant glioma MCTS lines when compared to IDH1-wild-type MCTS lines.

Supplementary Table S3 shows the rank order list of genes targeted by sgRNAs enriched in the genome-wide CRISPR/Cas9 knockout screens.

List of supplementary figures and tables.

5mC levels in primary AML and primary glioma samples and in MCTS lines.

Purpura fulminans (PF) is a rare but devastating complication of sepsis characterized by a highly thrombotic subtype of disseminated intravascular coagulation (DIC). A medical emergency, PF cases often require the involvement of consultant hematologists to assist with diagnosis and management of patients who are in a highly dynamic and deteriorating clinical situation. Patients who survive past the first 24 to 72 hours often die from complications of unchecked thrombosis rather than from shock, and survivors are usually left with severe scarring and tissue loss. Despite these challenging features, PF is a pathophysiologically distinct, homogenous, and highly predictable form of sepsis-associated DIC for which poor outcomes are not a foregone conclusion. The fundamental pathologic lesion in PF is a failure of the anticoagulant protein C pathway, which leads to uncontrolled microvascular clotting and inadequate protein C-mediated cytoprotective effects, which are vital for survival in sepsis. Herein, we review the clinical features and diagnosis of PF. Drawing from the existing clinical literature and from recent advances in our understanding of the pathophysiology of PF, we describe rationally-designed treatment approaches for this disorder, including repletion of natural circulating anticoagulants, use of therapeutic anticoagulation, and ways to optimize transfusion support, and we outline specific interventions that we would recommend avoiding.

The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an unexpected function. GAA accumulates in GAMT deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABA A receptors and causing depolarizing GABA currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a new mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

Characterization of isogenic IHA cell lines.

Supplementary Table S9 shows the gene set enrichment analysis gene set that corresponds to Figure S6A.

Supplementary Table S6 shows the mutational profiles of the primary AML patient samples subjected to H3K4me3 ChIP-seq.

Supplementary Table S11 shows the characteristics of the primary glioma patient samples.

Supplementary Table S10 shows the gene set enrichment analysis gene set that corresponds to Figure S6B.

Prolonged exposure to MLL inhibitor VTP50469 does not affect the proliferation of TF-1 cells grown under cytokine-rich conditions.

Characterization of KDM5A mutants.

Supplementary Table S2 shows the quantification of (R)-2HG in TF-1 cells.