Adult T-Cell Leukemia/Lymphoma Diagnosed in North American Is Characterized By a Requirement for BCL6 and a Cell Cycle Program Associated with DNA Replication Stress

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive disease of malignant CD4+ T cells that develops in human T-lymphotropic virus-1 (HTLV-1) carriers. Patients diagnosed with ATLL have the worst survival among all peripheral T-cell lymphomas. At the moment, no outcome-changing targeted therapy is available for ATLL highlighting an urgent need for in-depth understanding of its pathogenesis and development of new treatment strategies. We and others have shown that ATLLs diagnosed in the Japanese (J-ATLL) and North American (NA-ATLL) patients have very different clinical behavior, with the NA-ATLL variant characterized by a higher rate of chemo-refractory disease and worse prognosis. Differences are also seen in the somatic mutation patterns and responsiveness to an immune checkpoint blockade therapy, Nivolumab.

To explore additional aspects of ATLL biology where NA-ATLL and J-ATLL may exhibit distinct characteristics, we examined immunophenotypic features of 5 J-ATLL cell lines and cultures from 7 NA-ATLL patients using a panel of 17 flow cytometry markers. Our results show that, while the J-ATLL cell lines have a surface marker profile resembling classic regulatory T (Treg) cells, NA-ATLL samples are more similar to follicular T regulatory (Tfr) cells. This conclusion is also supported by GSEA analysis of of bulk RNA-seq. Consistent with a Tfr-like phenotype, NA-ATLL samples are characterized by more frequent expression of PD-1 and variable levels of BCL6. We also detected BCL6 in patient biopsy samples by IHC. Interestingly, although some J-ATLL cell lines express BCL6 as well, only NA-ATLL but not J-ATLL cell lines are sensitive to the BCL6-specific inhibitor FX1. Inactivating BCL6 by either FX1 treatment or siRNA-mediated BCL6 knock-down in NA-ATLL cells triggered rapid activation of the DNA damage response and death of S phase cells. These results suggest that in transformed NA-ATLL cells, BCL6 promotes survival by suppressing replication stress. Our experiments also demonstrate that compared to J-ATLL cell lines, NA-ATLL cell lines are more sensitive to S phase-targeting drugs including Wee1i (AZD-1775), ATRi (AZD-6738), and PARPi (Olaparib). These results support the concept that the cell cycle S phase is an Achilles’ Heel of NA-ATLL cells and an attractive therapeutic target.

In summary, despite the involvement of the same HTLV-1 subtype (HTLV-1a) in ATLLs diagnosed in Japan and North America, these two ATLL variants have distinct features in clinical behavior, mutational landscape, and immunophenotype. Our experiments described here point to additional differences in the cell cycle program and roles played by BCL6. Further studies are needed to fully characterize the cellular phenotype of NA-ATLL and develop S phase-based targeting strategies to treat this devastating disease.

Janakiram:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sica:Curios: Honoraria; AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb Foundation: Research Funding; Kite Pharma: Research Funding; Miragen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; PER Physician's Education Review.: Consultancy, Honoraria.