OncIndLymph · Oncogene-induced DNA damage as driver of B cell lymphoma genesis

Oncogene-induced DNA damage as driver of B cell lymphoma genesis

Acute lymphoblastic leukemia (ALL) is a leading cause of cancer-related death in children and young adults. It arises predominantly from immature precursors of the antibody producing B-cells. ALL is associated with recurrent genomic rearrangements that classify leukemia subgroups, and that in many cases have been shown to initiate and drive the disease. Besides initiating lesions, ALL genomes harbor additional alterations that are important for B-ALL cells. The most prominent defects in B-cell lineage leukemia (i.e. B-ALL) affect B-lineage specific genes that guide hematopoietic differentiation and function in healthy cells. Defects at these genes counteract normal differentiation towards antibody producing cells, increase cell metabolism, and promote de-regulation of normal gene expression; thereby promoting the malignant properties of leukemia cells. As reasons for genomic damage that could promote secondary genomic lesions, the antibody diversifying enzymes AID and RAG1 have been described. Besides, leukemia induction and progression is associated with activation of oncogenes (e.g. BCR-ABL1, MYC, TAL1) and cellular stress resulting from oncogene activation (i.e. oncogenic stress) is known to promote DNA damage. Indeed, while expression of the BCR-ABL1 oncogene efficiently induces malignant transformation of healthy B-cell precursors towards leukemia, successful transformation by BCR-ABL1 is preceded by a phase of cellular crisis. It was yet unclear, however, whether DNA damage occurs during this crisis stage, whether this DNA damage could promote the genomic lesions described for B-ALL patients, and whether an adaption of secondary genomic lesions is at all important for the initial establishment of malignancy. To investigate these open questions we first analyzed global DNA damage in primary B-cell precursors upon acute induction of leukemia-inducing oncogenes such as BCR-ABL1 and C-MYC. We identified >1000 sensitive genomic regions using next generation sequencing (NGS) based methods and analyses using independent techniques supported that these regions become genetically instable in oncogene expressing B-cell precursors. We further showed that oncogene-induced genetic instability occurs at highly expressed genes that are enriched for DNA sequences known to promote conflicts between transcription of genes and genome replication, and that consecutively favor DNA damage. As lineage specific genes are highly transcribed in B-cell precursors, the most prominent DNA regions affected by oncogene-induced fragility were B-cell lineage specific genes i.e. the genes that are most prominently altered in human B-ALL. As a proof of principle, we further showed that conversion of leukemic B-cell precursors toward the myeloid cell lineage resulted in increased fragility of myeloid gene loci. Hence, we demonstrated that oncogenic stress in B-cell precursors predisposes lineage-specific genes to DNA damage, which likely contributes to their frequent alteration in B-ALL leukemia cells (published in Boulianne et al., 2017 Cell Reports). When analyzing DNA damage and transcription in oncogene expressing B-cell precursors, we further noticed an upregulation of DNA damage response proteins during the oncogenic stress response. Functional analysis of upregulated factors revealed their essential function in transformed cells to suppress genome fragility. A manuscript describing these findings is currently in preparation. Lastly, we investigated the occurrence and positive selection for genomic alterations during BCR-ABL1-induced malignant transformation using Exome-Seq. While we identified genomic lesions in lineage specific genes, positively selected clonal alterations exclusively related to tumor suppressor genes, hence indicating that the most prominent genetic lesions found in B-ALL patients are not required for disease initiation but rather play a role in disease progression. Also here, a manuscript describing our results is currently in preparation. The above-described achievements were a direct result of the CIG grant, which allowed me to support my research team and establish my group within the Department of Medicine at Imperial College London.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз