Key Points North American ATLL has a distinct genomic landscape with a high frequency of prognostic epigenetic mutations, including EP300 mutations. ATLL samples with mutated EP300 have compromised p53 function and are selectively sensitive to decitabine treatment.

Diffuse large B-cell lymphomas (DLBCLs) contain 2 major molecular subtypes; namely, the germinal center B-cell-like (GCB) and the activated B-cell-like (ABC) DLBCLs. It is well documented that ABC-DLBCL cases have a significantly poorer survival response than GCB-DLBCLs in both the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and the rituximab (R)-CHOP eras. However, the underlying cause of this subtype disparity is poorly understood. Nevertheless, these clinical observations raise the possibility for an ABC-DLBCL-specific resistance mechanism that is directed toward 1 of the CHOP components and is inadequately addressed by rituximab. Here, we report that the main cytotoxic ingredient in CHOP, doxorubicin (Dox), has subtype-specific mechanisms of cytotoxicity in DLBCLs resulting from differences in the subcellular distribution pattern. Specifically, in cell line models of ABC-DLBCL, Dox is often enriched in the cytoplasm away from the nuclear DNA. As a result, Dox-induced cytotoxicity in ABC-DLBCLs is often dependent on oxidative stress, rather than DNA damage response. These findings are corroborated by gene signature analysis, which demonstrates that basal oxidative stress status predicts treatment outcome among patients with ABC-DLBCL, but not patients with GCB-DLBCL. In terms of redox-related resistance mechanism, our results suggest that STAT3 confers Dox resistance in ABC-DLBCLs by reinforcing an antioxidant program featuring upregulation of the SOD2 gene. Furthermore, a small-molecule STAT3 inhibitor synergizes with CHOP to trigger oxidative stress and kill ABC-DLBCL cells in preclinical models. These results provide a mechanistic basis for development of novel therapies that target either STAT3 or redox homeostasis to improve treatment outcomes for ABC-DLBCLs.

Purpose: To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models. Experimental Design: Frequency and prognostic impact of PAK2 amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and in vivo xenograft models were developed using primary ATLL cells from North American patients. Two PAK inhibitors were used to block PAK kinase activity pharmacologically. siRNA-based gene silencing approach was used to genetically knockdown (KD) PAK1 and PAK2 in ATLL cell lines. Results: PAK1/2/4 are the three most abundantly expressed PAK family members in ATLL. PAK2 amplifications are seen in 24% of ATLLs and are associated with worse prognosis in a large patient cohort. The pan-PAK inhibitor PF-3758309 (PF) has strong in vitro and in vivo activity in a variety of ATLL preclinical models. These activities of PF are likely attributed to its ability to target several PAK isoforms simultaneously because genetic silencing of either PAK1 or PAK2 produced more modest effects. PAK2 plays a major role in CADM1-mediated stromal interaction, which is an important step in systemic dissemination of the disease. This finding is consistent with the observation that PAK2 amplification is more frequent in aggressive ATLLs and correlates with inferior outcome. Conclusions: PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Taken together, PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs.

Bach2 is a transcription factor required for affinity maturation of B cells. A recent study reveals, quite unexpectedly, that Bach2 also plays a key role in the pre-B cell receptor checkpoint and functions as a tumor suppressor in pre-B cell acute lymphocytic leukemia.