SIGNIFICANCE: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.
Recently, high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements have been categorized separately from diffuse large B-cell lymphoma or BL.
Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH).
Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas.
The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.
The treatment of BL cells with decitabine reduced methylation, induced miR‑29s expression and downregulated MYC protein levels in a dose‑dependent manner.
Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
The phosphatidylinositol 3-kinase (PI3K)/RAC-α serine/threonine-protein kinase (AKT) pathway is constitutively activated in a number of lymphoid malignancy types, including diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma.
However, ectopic IRF4 expression can augment EBV lytic gene expression induced by anti-immunoglobulin (anti-Ig) or sodium butyrate treatment in all tested lymphoma cells, whereas IRF4 knockout in Raji cells, the only BL cell line with detectable endogenous IRF4 expression, abolishes EBV lytic gene expression induced by anti-Ig, and this is accompanied by the reduction of Blimp-1 expression, whose overexpression, in turn, can rescue EBV lytic gene expression in IRF4 knockout Raji cells.
Based on drug response, we identified cell line specific sensitivities, i.e. to venetoclax driven by BCL2 overexpression and partitioned subsets of BL driven by response to kinase inhibitors.
Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development, we demonstrate proproliferative and antiapoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B-cell-derived lymphomagenesis.
Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma.
Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development, we demonstrate proproliferative and antiapoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B-cell-derived lymphomagenesis.
We investigated the activation of the PI3K/AKT pathway in a cell line model of resistant BL and the ability to target this pathway with small molecule inhibitors in BL cell lines.
We investigated the activation of the PI3K/AKT pathway in a cell line model of resistant BL and the ability to target this pathway with small molecule inhibitors in BL cell lines.
We investigated the activation of the PI3K/AKT pathway in a cell line model of resistant BL and the ability to target this pathway with small molecule inhibitors in BL cell lines.
Burkitt lymphoma in Iraqi children: A distinctive form of sporadic disease with high incidence of EBV<sup>+</sup> cases and more frequent expression of MUM1/IRF4 protein in cases with head and neck presentation.
Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development, we demonstrate proproliferative and antiapoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B-cell-derived lymphomagenesis.
Therefore, to identify targets of LMP1 that are regulated through PARP1, LMP1 was ectopically expressed in an EBV-negative Burkitt's lymphoma cell line.