Biology subjects

Velloso, E. D. R. P.

Publications and source records attributed to Velloso, E. D. R. P..

2 recordsLinked to original sources

bioRxiv2022

The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy

Treatment of acute leukemia is challenging due to genetic heterogeneity between and even within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently lead to relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 proteins (PIP4K2s) inhibition demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncover the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagy flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax in resistant leukemic models. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 was associated with mitochondrial metabolism, cell cycle, cell-of-origin, and the TP53 pathway. Minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggested a favorable therapeutic window. Our study provides insight into pharmacological inhibition of PIP4Ks targeting mitochondrial homeostasis and autophagy shedding light on a new class of drugs for acute leukemias.

pharmacology and toxicology↗

bioRxiv2021

Clonal hematopoiesis in individuals with ANKRD26 or ETV6 germline mutations

Currently, there are at least a dozen recognized hereditary hematopoietic malignancies (HHMs), some of which phenocopy others. Among these, three HHMs driven by germline mutations in ANKRD26, ETV6, or RUNX1 share a phenotype of thrombocytopenia, qualitative platelet defects, and an increased lifetime risk of hematopoietic malignancies (HMs). Prior work has demonstrated that RUNX1 germline mutation carriers experience an elevated lifetime risk (66%) for developing clonal hematopoiesis (CH) prior to age 50. Germline mutations in ANKRD26 or ETV6 phenocopy RUNX1 germline mutations, but no studies have focused on the risk of CH in individuals with germline mutations in ANKRD26 or ETV6. To determine the prevalence of CH in individuals with germline mutations in ANKRD26 or ETV6, we performed next generation sequencing on hematopoietic tissue from twelve individuals with either germline ANKRD26 or germline ETV6 mutations. Each patient had thrombocytopenia but had not developed HMs. Among the seven individuals with germline ANKRD26 mutations, one patient had a CH clone driven by a somatic SF3B1 mutation (p.Lys700Glu). This mutation increased from a variant allele frequency (VAF) of 9.4% at age 56 to 17.4% at age 60. None of the germline ETV6 mutation carriers had evidence of CH at the limits of detection of the NGS assay (5% VAF). Unlike individuals with germline mutations in RUNX1, no individuals under the age of 50 with germline mutations in ANKRD26 or ETV6 had detectable CH. This work demonstrates that ANKRD26 germline mutation carriers, but not ETV6 mutation carriers, experience elevated risk for CH.

genetics↗