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1.
J Proteome Res ; 23(6): 2169-2185, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38804581

ABSTRACT

Quantitative proteomics has enhanced our capability to study protein dynamics and their involvement in disease using various techniques, including statistical testing, to discern the significant differences between conditions. While most focus is on what is different between conditions, exploring similarities can provide valuable insights. However, exploring similarities directly from the analyte level, such as proteins, genes, or metabolites, is not a standard practice and is not widely adopted. In this study, we propose a statistical framework called QuEStVar (Quantitative Exploration of Stability and Variability through statistical hypothesis testing), enabling the exploration of quantitative stability and variability of features with a combined statistical framework. QuEStVar utilizes differential and equivalence testing to expand statistical classifications of analytes when comparing conditions. We applied our method to an extensive data set of cancer cell lines and revealed a quantitatively stable core proteome across diverse tissues and cancer subtypes. The functional analysis of this set of proteins highlighted the molecular mechanism of cancer cells to maintain constant conditions of the tumorigenic environment via biological processes, including transcription, translation, and nucleocytoplasmic transport.


Subject(s)
Neoplasms , Proteomics , Humans , Cell Line, Tumor , Proteomics/methods , Neoplasms/metabolism , Neoplasms/genetics , Neoplasms/pathology , Proteome/analysis , Proteome/metabolism
2.
Leukemia ; 38(5): 969-980, 2024 May.
Article in English | MEDLINE | ID: mdl-38519798

ABSTRACT

The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eµ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eµ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eµ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.


Subject(s)
Disease Models, Animal , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Animals , Mice , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Aneuploidy , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Centrosome/pathology , Diploidy
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