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  • 1
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 3, No. 1 ( 2022-01-01), p. 16-31
    Abstract: Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing as well as transcriptional and proteomic profiling of paired leukemia-infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS-infiltrating cells, including complement component 3 (C3), and drug targeting of C3 influenced CNS disease in xenografts. CNS-infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies targeting of mRNA translation as a potential therapeutic approach for B-ALL leptomeningeal disease. Significance: Cancer metastases are often driven by distinct subclones with unique biological properties. Here we show that in B-ALL CNS disease, the leptomeningeal environment selects for cells with unique functional dependencies. Pharmacologic inhibition of mRNA translation signaling treats CNS disease and offers a new therapeutic approach for this condition. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2643-3230 , 2643-3249
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2022
    In:  Blood Cancer Discovery Vol. 3, No. 3 ( 2022-05-05), p. 208-219
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 3, No. 3 ( 2022-05-05), p. 208-219
    Abstract: Cancers are composed of genetically distinct subpopulations of malignant cells. DNA-sequencing data can be used to determine the somatic point mutations specific to each population and build clone trees describing the evolutionary relationships between them. These clone trees can reveal critical points in disease development and inform treatment. Pairtree is a new method that constructs more accurate and detailed clone trees than previously possible using variant allele frequency data from one or more bulk cancer samples. It does so by first building a Pairs Tensor that captures the evolutionary relationships between pairs of subpopulations, and then it uses these relations to constrain clone trees and infer violations of the infinite sites assumption. Pairtree can accurately build clone trees using up to 100 samples per cancer that contain 30 or more subclonal populations. On 14 B-progenitor acute lymphoblastic leukemias, Pairtree replicates or improves upon expert-derived clone tree reconstructions. Significance: Clone trees illustrate the evolutionary history of a cancer and can provide insights into how the disease changed through time (e.g., between diagnosis and relapse). Pairtree uses DNA-sequencing data from many samples of the same cancer to build more detailed and accurate clone trees than previously possible. See related commentary by Miller, p. 176. This article is highlighted in the In This Issue feature, p. 171.
    Type of Medium: Online Resource
    ISSN: 2643-3230 , 2643-3249
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
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