Potency and efficacy of pharmacological PIP4K2 inhibitors in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), a complex malignancy, displays varying expression profiles of PIP4K2-related genes in adult patients. While PIP4K2A expression is elevated in ALL bone marrow cells compared to healthy bone marrow cells, PIP4K2B is downregulated, and PIP4K2C remains relatively unchanged. Despite the correlation between increased PIP4K2A expression and increased percentage of peripheral blood blasts, clinical outcomes do not strongly correlate with the expression of these genes. Here we investigated the therapeutic potential of three PIP4K2 inhibitors (THZ-P1-2, a131, and CC260) in ALL cell models. THZ-P1-2 emerges as the most effective inhibitor, inducing cell death and mitochondrial damage while reducing cell viability and metabolism significantly. Comparative analyses highlight the superior efficacy of THZ-P1-2 over a131 and CC260. Notably, THZ-P1-2 uniquely disrupts autophagic flux and inhibits the PI3K/AKT/mTOR pathway, indicating a distinct molecular mechanism. In summary, our findings elucidate the differential expression of PIP4K2-related genes in ALL and underscore the potential role of PIP4K2A in disease pathogenesis. The therapeutic promise of THZ-P1-2 in ALL treatment, along with its distinct effects on cell death mechanisms and signaling pathways, enriches our understanding of PIP4K2's involvement in ALL development and offers targeted therapy prospects.

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

The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently 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 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered 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 the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.

Predictive factors associated with induction-related death in acute myeloid leukemia in a resource-constrained setting.

Despite advances in supportive measures, acute myeloid leukemia (AML) remission induction still has a high mortality rate in real-world studies as compared to prospective reports. We analyzed data from 206 AML adult patients treated with conventional chemotherapy. The primary endpoint was the 60-day mortality rate, aiming to find risk factors and to examine the role of anti-infection prophylaxis. The 60-day mortality rate was 26%, raising to 41% among those older than 60 years. Complete response was documented at the end of induction in 49%. The final survival model showed that age > 60 years (HR 3.2), Gram-negative colonization (HR 3), monocytic AML (HR 1.8), C-reactive protein (CRP) > 15 mg/dL (HR 10), and an adverse risk in the genetic stratification (HR 3) were associated with induction death. Multidrug-resistant bacteria colonization, thrombosis, and AKI were documented in 71%, 12%, and 66% of the cohort, respectively. Antibacterial and antifungal prophylaxis did not improve outcomes in this study. Our report corroborated the higher mortality during AML induction compared to real-world data from the USA and Europe. In line with other publications, age and cytogenetic stratification influenced early death in this cohort. Noticeably, Gram-negative colonization, monocytic AML, and CRP were also significant to early mortality.

Risk factors and incidence of thrombosis in a Brazilian cohort of patients with Philadelphia-negative myeloproliferative neoplasms.

Few data are available regarding epidemiology and outcomes of Philadelphia-negative chronic myeloproliferative neoplasms (MPN) in Latin America. Therefore, current models for MPN treatment are based in large cohorts of patients from Europe and North America. In this paper, we conducted a retrospective study to evaluate thrombotic and bleeding events in a cohort of patients with MPN from a reference center in Brazil. A total of 334 patients were included, being essential thrombocythemia the most common diagnosis. Here, we found that 41% of the MPN patients had a thrombotic event prior to the diagnosis. Thrombosis was more frequent in patients under 60 years-old. In a multivariable model, only JAK2 V617F mutation (OR 2.57 95% CI 1.58-4.18, p < 0.001) and presence of two cardiovascular risk factors (OR 1.90 95% CI 1.21-2.98, p < 0.005) were significant for thrombosis. The risk of thrombosis was similar among all subtypes of MPN. Cumulative incidence of thromboembolic event at 5 years from diagnosis was 5.8% (95% CI 3.5-8.9), which is similar to previous studies. The high incidence of thromboembolic events in younger patients suggests that socioeconomic disparities might have a role in the outcomes of MPN.