BL-41

TCF3 and ID3 Regulate TSPAN32 Expression in Burkitt Lymphoma

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma driven by MYC overexpression due to chromosomal translocations, with subtypes showing distinct clinical features. TSPAN32, a member of the tetraspanin family, is important in B-cell development. However, the expression and regulation of TSPAN32 in BL are not well understood. Scuderi et al. investigated the expression of TSPAN32 in BL subtypes and the mechanisms responsible for TSPAN32 dysregulation

They analyzed TSPAN32 expression in BL subtypes and found it was downregulated regardless of EBV status. In order to gain an understanding of the mechanisms that may be responsible for the regulation of TSPAN32 expression, the authors explored the role of TCF3 and ID3 in three BL cell lines (Namalwa, Daudi, and BL41). ID3 mutations (truncating) were found in both Daudi and BL41 cells (Fig. 1A). Both TCF3 knockdown and ectopic induction of functional ID3 decreased proliferation, with the most significant decrease in Daudi and BL41 cells (Fig. 2B). Using PCR, they confirmed a decrease in TCF3 (64.6%) and an increase in ID3 (31.1%). They also found that knockdown of TCF3 and overexpression of ID3 had no effect on TSPAN32 in Namalwa cells (Fig. 1C and D).

Karonudib Has Potent Anti-Tumor Effects in Preclinical Models of B-Cell Lymphoma

Despite advances in chemo-immunotherapy, relapsed/refractory B-cell lymphomas (e.g., DLBCL, Burkitt lymphoma, and mantle cell lymphoma) remain a major clinical challenge. MTH1, an enzyme preventing oxidized DNA damage, is upregulated in these cancers, making it a promising therapeutic target. In this regard, Oksvold et al. evaluated the preclinical characteristics of karonudib (TH1579) to assess its potential as a treatment for B-cell lymphoma as an MTH1 inhibitor.

Viability, DNA damage (incorporation of 8-oxo-dGTP), and cell cycle arrest were assessed in vitro. Cell viability staining and TUNEL assays indicated that karonudib treatment led to high levels of apoptotic cells (>50% at 24 h), with little evidence of necrosis in three karonudib-sensitive lymphoma cell lines (Fig. 2B, C). In cell cycle experiments, G2/M arrest was induced as early as 6–12 h after treatment, and this effect was prolonged until 24 h in Mino cells, in contrast to DoHH-2 cells, which instead shifted into G1 arrest (Fig. 2D, E). Apoptosis was induced from G2/M in TP53-mutant lines (Mino, BL-41) but also from G1 in TP53-wild-type DoHH-2 (Fig. 2E). Microscopy studies indicated that this arrest was prometaphase due to failure of spindle assembly, as evidenced by monopolar spindles and the absence of anaphase cells (Fig. 2F). No significant increase in ɣH2AX was observed, which indicated that the cell cycle arrest was not due to replication stress. Differential expression and gene set enrichment analyses were also performed, which indicated dysregulation of "mitotic spindle" and "G2/M arrest" gene sets (Fig. 2G), which was in agreement with the flow cytometry studies.