Approximately 9% of pediatric acute T-cell lymphoid leukemias (T-ALL) present a mutation with insertion of a cysteine residue in the justamembrane portion of the IL7Ra receptor, which leads to homodimerization and constitutive JAK / STAT signaling, contributing to leukemogenesis. The mutations are concentrated in a 26bp stretch of exon 6 of the IL7R gene (hotspot) and are characterized by large insertions. IL7R is also mutated in a portion of cases of LLA-B-derived from the philapdelphia-like subtype. In addition, a new class of mutations in IL7R has recently been described, characterized by the insertion of positively charged amino acids in the same portion of the receptor (+ EJM). The + EJM mutations do not lead to the homodimerization of the receptor, but cause a hypersensitization of the same, which leads to greater signaling of the JAK / STAT pathway. The analysis of the mutations suggests that they start with double-strand breaks, followed by repair via NHEJ (non-homologous end joining). Previous results show that breaks in the IL7R hotspot generated by CRISPR-Cas9 are sufficient to generate insertions similar to those observed in T-ALL patients. It was also observed that the TdT (Terminal deoxynucleotidyl Transferase) polymerase, specific for lymphocytes, plays an important role in these insertions. In addition, cryptic RSS sites, recognized by RAGs, were found in the IL7R genomic sequence, which may explain the origin of these mutations. The main purpose of this work is to investigate whether double-strand breaks in the mouse Il7r hotspot are sufficient to develop ALL, and also to investigate the possible roles of TdT and RAG1 / 2 in this mutagenic process.
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