Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice
The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longst...
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Published in | Nature communications Vol. 14; no. 1; p. 5159 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
24.08.2023
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant
Pax5
+/−
B-cell precursors toward leukemia. Transcriptional profiling reveals that
Myd88
is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of
Myd88
expression leads to a significant increase in leukemia incidence in
Pax5
+/−
Myd88
+/−
mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in
Pax5
+/−
mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.
Immunological stressors are linked to the transformation of preleukemic B cells to B-cell acute lymphoblastic leukemia. Here the authors show a dysregulation of innate immune signaling in preleukemic precursor B cells and link to the development of B-cell acute lymphoblastic leukemia in a murine model. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-023-40961-z |