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Data from Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution in BCR-ABL1–Driven B-Cell Lineage Acute Lymphoblastic Leukemia
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Data from Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution in BCR-ABL1–Driven B-Cell Lineage Acute Lymphoblastic Leukemia
Data from Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution in BCR-ABL1–Driven B-Cell Lineage Acute Lymphoblastic Leukemia
TG
Tanja Andrea Gruber
Tanja Andrea Gruber
MC
Mi Sook Chang
Mi Sook Chang
RS
Richard Sposto
Richard Sposto
MM
Markus Müschen
Markus Müschen
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30 March 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/0008-5472.c.6500639.v1
Abstract
Activation-induced cytidine deaminase (AID) is required for somatic hypermutation and immunoglobulin (Ig) class switch recombination in germinal center (GC) B cells. Occasionally, AID can target non-Ig genes and thereby promote GC B-cell lymphomagenesis. We recently showed that the oncogenic BCR-ABL1 kinase induces aberrant expression of AID in pre-B acute lymphoblastic leukemia (ALL) and lymphoid chronic myelogenous leukemia blast crisis. To elucidate the biological significance of aberrant AID expression, we studied loss of AID function in a murine model of BCR-ABL1 ALL. Mice transplanted with BCR-ABL1–transduced AID−/− bone marrow had prolonged survival compared with mice transplanted with leukemia cells generated from AID+/+ bone marrow. Consistent with a causative role of AID in genetic instability, AID−/− leukemia had a lower frequency of amplifications and deletions and a lower frequency of mutations in non-Ig genes, including Pax5 and Rhoh compared with AID+/+ leukemias. AID−/− and AID+/+ ALL cells showed a markedly distinct gene expression pattern, and AID−/− ALL cells failed to downregulate a number of tumor-suppressor genes including Rhoh, Cdkn1a (p21), and Blnk (SLP65). We conclude that AID accelerates clonal evolution in BCR-ABL1 ALL by enhancing genetic instability and aberrant somatic hypermutation, and by negative regulation of tumor-suppressor genes. Cancer Res; 70(19); 7411–20. ©2010 AACR.
Keywords
SOMATIC
BONE MARROW
LEUKEMIA
GENE EXPRESSION
BCR ABL1
ACCELERATES CLONAL EVOLUTION
EVOLUTION IN BCR
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