IGH/MYC Translocation in Burkitt Lymphoma Is Associated with BRCA2 Deficiency and Synthetic Lethality By PARP1 Inhibitors

Burkitt lymphoma/leukemia (BL) is a highly aggressive mature B-cell neoplasm characterized by chromosomal rearrangements of the c-myc oncogene resulting in the overexpression of MYC transcription factor. The most common translocation is the t(8;14)(q24;q32) (85% of all cases), which involves MYC and IGH loci to generate IGH/MYC. Deregulation of MYC, a potent proto-oncogene and transcriptional regulator contributes to lymphomagenesis through alterations in cell cycle regulation, and cell differentiation, apoptosis, adhesion, and metabolism.

BL treatment consists of high-intensity chemotherapy protocols that include cyclophosphamide, cytarabine (AraC) and doxorubicin. Current therapies have achieved a very favorable outcome resulting in complete remission in 75% to 90% of BL patients and a survival rate of 70% to 80%. However the current treatment for BL is suboptimal in elderly patients or patients with advanced-stage diseased, in the setting of HIV infections, as well as in the setting of relapsed disease. Therefore new therapeutic strategies are necessary to improve the outcomes in BL diseases in the poor prognosis patients.

It has been reported that overexpression of MYC caused accumulation of potentially lethal DNA double-strand breaks (DSBs), which can modulate the response of tumor cells to genotoxic treatment. Therefore, we examined the consequences of DSBs accumulation in IGH/MYC-positive BL cells. Here we show that untreated and cytarabine (AraC)-treated IGH/MYC-positive BL cells accumulate high number of potentially lethal DNA double-strand breaks (DSBs) and display downregulation of BRCA2 tumor suppressor protein, which is a key element of homologous recombination - mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro. Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary BL xenografts.

In conclusion, we postulate that BRCA2 deficiency may predispose BL cells to synthetic lethality triggered by PARP1 inhibitor, such as recently FDA approved olaparib. Moreover, PARP1 inhibitor may be useful for the treatment of other malignancies associated with deregulation of MYC, including diffuse large B-cell lymphoma (DLBCL) and ALK-positive LBCL.