ABSTRACT
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.
Subject(s)
Phosphotransferases (Alcohol Group Acceptor) , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Phosphotransferases (Alcohol Group Acceptor)/genetics , Cell Line, Tumor , Signal Transduction/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Autophagy/drug effects , Cell Survival/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Apoptosis/drug effectsABSTRACT
Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P2, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses.
Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Humans , Cell Line, Tumor , Proto-Oncogene Proteins c-bcl-2/metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Apoptosis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Phosphotransferases (Alcohol Group Acceptor)/pharmacologyABSTRACT
ABSTRACT Introduction: Systemic Mastocytosis comprises a group of neoplastic diseases characterized by clonal expansion and infiltration of mast cells into several organs. The diagnosis and treatment of this disease may be challenging for non-specialists. Objective: Make suggestions or recommendations in Systemic Mastocytosis based in a panel of Brazilian specialists. Method and results: An online expert panel with 18 multidisciplinary specialists was convened to propose recommendations on the diagnosis and treatment of Systemic Mastocytosis in Brazil. Recommendations were based on discussions of topics and multiple-choice questions and were graded using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence Chart. Conclusion: Twenty-two recommendations or suggestions were proposed based on a literature review and graded according to the findings.
Subject(s)
Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/therapy , Child , AdultABSTRACT
INTRODUCTION: Systemic Mastocytosis comprises a group of neoplastic diseases characterized by clonal expansion and infiltration of mast cells into several organs. The diagnosis and treatment of this disease may be challenging for non-specialists. OBJECTIVE: Make suggestions or recommendations in Systemic Mastocytosis based in a panel of Brazilian specialists. METHOD AND RESULTS: An online expert panel with 18 multidisciplinary specialists was convened to propose recommendations on the diagnosis and treatment of Systemic Mastocytosis in Brazil. Recommendations were based on discussions of topics and multiple-choice questions and were graded using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence Chart. CONCLUSION: Twenty-two recommendations or suggestions were proposed based on a literature review and graded according to the findings.
Subject(s)
Leukemia, Myeloid, Acute/diagnosis , Mastocytosis, Systemic/diagnosis , Adult , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Male , Mastocytosis, Systemic/genetics , Mastocytosis, Systemic/metabolism , Mastocytosis, Systemic/pathology , Mutation , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolismABSTRACT
Cerebrovascular disease (CVD) is a severe complication associated with sickle cell anemia. Abnormal transcranial Doppler (TCD) identifies some children at high risk, but other markers would be helpful. This cohort study was aimed at evaluating the effects of genetic biomarkers on the risk of developing CVD in children from Minas Gerais, Brazil. Clinical and hematological data were retrieved from children's records. Outcomes studied were overt ischemic stroke and CVD (overt ischemic stroke, transient ischemic attack, abnormal TCD, or abnormal cerebral angiography). Out of 411 children, 386 (93.9%) had SS genotype, 23 (5.6%) had Sß(0)-thal and two had severe Sß(+)-thal (0.5%). Frequency of CVD was lower in Sß-thal group (p=0.05). No effect of VCAM-1 polymorphism on stroke or CVD risks was detected. Cumulative incidence of stroke was significantly higher for children with TNF-α A allele (p=0.02) and lower for children with HBA deletion (p=0.02). However, no association between CVD and TNF-α -308G>A was found. CVD cumulative incidence was significantly lower for children with HBA deletion (p=0.004). This study found no association between VCAM1 c.1238G>C and stroke. An association between stroke and TNF-α -308A allele has been suggested. Our results have confirmed the protective role of HBA deletion against stroke and CVD.