Deletion of Non-core Regions of RAG1 and RAG2 Accelerates Leukemogenesis and Increases Off-target V(D)J Recombination in BCR-ABL1-driven B Cell Lineage Lymphoblastic Leukemia

Kernekoncepter

The non-core regions of RAG1 and RAG2 play a crucial role in maintaining the accuracy of V(D)J recombination and genomic stability in BCR-ABL1+ B cell leukemia.

Resumé

The study investigated the impact of deleting the non-core regions of RAG1 and RAG2 on the development and progression of BCR-ABL1+ B cell leukemia in mouse models.
Key highlights:

Leukemic cells lacking the non-core regions of RAG1 (cRAG1) or RAG2 (cRAG2) exhibited more aggressive disease characteristics compared to those with full-length RAG (fRAG).
cRAG leukemic cells showed higher frequencies of off-target V(D)J recombination and oncogenic mutations compared to fRAG.
The deletion of the non-core RAG1 region resulted in reduced RAG cleavage accuracy and smaller recombinant sizes, potentially contributing to the increased off-target V(D)J recombination in cRAG1 leukemic cells.
The findings suggest that the non-core regions, particularly of RAG1, play a crucial role in preserving V(D)J recombination precision and genomic stability in BCR-ABL1+ B cell leukemia.

Statistik

Leukemic cells from cRAG1 and cRAG2 mice had lower survival rates compared to fRAG mice (median 39 or 57 days vs. 74.5 days, p < 0.0425).
cRAG leukemic cells exhibited significantly higher leukemia burdens in the peripheral blood, bone marrow, and spleen compared to fRAG.
cRAG leukemic cells had a higher fraction of cells in the S/G2-M phase of the cell cycle and reduced apoptosis rates compared to fRAG.
cRAG leukemic cells showed a more immature B cell phenotype with 91-98% being CD19+BP-1+B220+CD43+ large pre-B cells, compared to 65% in fRAG.
cRAG leukemic cells had a higher frequency of off-target V(D)J recombination events and oncogenic mutations compared to fRAG.

Citater

"The non-core regions of RAG1 and RAG2 play a significant role in preserving V(D)J recombination precision and genomic stability in BCR-ABL1+ B-ALL."
"The deletion of the non-core RAG1 region appears to constrict the size of off-target recombination, potentially contributing to the elevated frequency of off-target V(D)J recombination observed in cRAG1 leukemic cells."

Vigtigste indsigter udtrukket fra

RAG1 and RAG2 Non-core Regions Are Implicated in Leukemogenesis and Off-target V(D)J Recombination in BCR-ABL1-driven B-cell Lineage Lym-phoblastic Leukemia

by Yu,X., Zhou,... kl. www.biorxiv.org 10-02-2023

https://www.biorxiv.org/content/10.1101/2023.09.29.560132v2

Dybere Forespørgsler

What are the potential therapeutic implications of targeting the non-core regions of RAG1 and RAG2 in BCR-ABL1+ B cell leukemia?

The study highlights the significant role of non-core regions of RAG1 and RAG2 in maintaining the accuracy of V(D)J recombination and genomic stability in BCR-ABL1+ B cell leukemia. Targeting these non-core regions could potentially be a therapeutic strategy to modulate the activity of the RAG recombinase and reduce off-target V(D)J recombination. By specifically inhibiting or modifying the non-core regions of RAG1 and RAG2, it may be possible to regulate the cleavage accuracy and size of off-target recombination events, thereby reducing the risk of genomic instability and malignant transformation in BCR-ABL1+ B cell leukemia. This targeted approach could offer a novel therapeutic avenue for improving the treatment outcomes of this aggressive form of leukemia.

How do the findings from this study on the role of non-core RAG regions compare to their function in other subtypes of acute lymphoblastic leukemia?

The findings from this study shed light on the unique role of non-core RAG regions, particularly the non-core region of RAG1, in BCR-ABL1+ B cell leukemia. While the study focused on the impact of non-core RAG regions in this specific subtype of acute lymphoblastic leukemia, it is important to note that the function of non-core RAG regions may vary across different subtypes of the disease.
In other subtypes of acute lymphoblastic leukemia, the non-core regions of RAG1 and RAG2 may play distinct roles in regulating V(D)J recombination, genomic stability, and the development of malignant phenotypes. The study's findings provide valuable insights into the specific mechanisms through which non-core RAG regions influence off-target V(D)J recombination in BCR-ABL1+ B cell leukemia. Further research is needed to explore how these non-core regions function in other subtypes of acute lymphoblastic leukemia and whether similar mechanisms contribute to disease progression and genomic instability in those contexts.

Could the insights gained from this study on off-target V(D)J recombination be extended to understand the mechanisms of genomic instability in other hematological malignancies?

The insights gained from this study on off-target V(D)J recombination in BCR-ABL1+ B cell leukemia could potentially be extended to understand the mechanisms of genomic instability in other hematological malignancies. Off-target V(D)J recombination is a common source of genomic instability in various types of leukemia and lymphoma, leading to the generation of oncogenic structural variations and contributing to disease progression.
By studying the role of non-core RAG regions in regulating off-target V(D)J recombination and genomic stability, researchers can gain a deeper understanding of how similar mechanisms may operate in other hematological malignancies. The findings from this study provide a foundation for investigating the impact of RAG activity on genomic instability in different types of leukemia and lymphoma, offering insights into potential therapeutic targets and strategies for mitigating the effects of aberrant V(D)J recombination in these diseases.