CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans

PLoS Medicine
Ana-Carolina Martinez-TorresSantos A Susin

Abstract

Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides. In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in ...Continue Reading

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Citations

Mar 5, 2017·Immunological Reviews·Hanke L MatlungTimo K van den Berg
Dec 27, 2017·Journal of Cellular and Molecular Medicine·Gaiqing WangJiping Tang
May 12, 2018·Cell Death & Disease·Pascal LeclairChinten James Lim
Nov 22, 2018·Cancer Science·Ashanti Concepción Uscanga-PalomequeCristina Rodríguez-Padilla
Feb 12, 2020·Cancer Science·Pascal LeclairChinten James Lim
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Feb 23, 2020·Frontiers in Immunology·Wenting ZhangHua Jin
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Methods Mentioned

BETA
Assay
flow cytometry
PCR
transfection
xenograft
isothermal
microscale thermophoresis

Software Mentioned

FlowJo
Multi Gauge
Carestream Molecular Imaging
GraphPad
OriginLab
GraphPad Prism
ARRIVE
Origin
TILLvisION

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