Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2023 S470 TCL-330 RHOA G17V Potentiates CD28‑Induced NFAT Transcriptional Activity by Modulating p300 Activity: A Step Further in the Understanding of Follicular Helper T‑Cell Lymphoma David Vallois PhD1, Mélanie Juilland PhD2, Ioannidou Kalliopi PhD1, François Lemmonier MD PhD3, Edoardo Missiaglia PhD1, Bettina Bisig MD PhD1, Margot Thome PhD2, Laurence de Leval MD PhD1 1Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. 2Department of Immunobiology, University of Lausanne, Lausanne, Switzerland. 3Unité Hémopathies Lymphoïdes, Hôpitaux Universitaires Henri Mondor, Assistance Publique des Hôpitaux de Paris, Créteil, France Context: Follicular helper T-cell (TFH) lymphoma of the angioimmunoblastic type (AITL) carries highly recurrent RHOA G17V mutation (60-70% cases) and frequent mutations in other T-cell receptor (TCR) signaling-related genes (50% cases), including CD28 mutations, which often co-occur with RHOA G17V. Objective: We sought to elucidate the potential cooperation of RHOA and CD28 variants in sustaining T-cell activation. Design: We generated stable Jurkat T-cell lines expressing the wild type (wt) or G17V mutant form of RHOA in combination with either the wt or T195P variant form of CD28 and analyzed their responses to TCR and CD28 co-stimulation. Results: Concomitant expression of RHOA G17V and CD28 T195P variants induced significantly higher levels of interleukin 2 (IL-2) transcription and secretion than either variant alone upon cell stimulation with agonistic antiCD3 and anti-CD28 antibodies. The combination of both variants also induced significantly higher levels of NFAT transcriptional activity than either variant alone. We further dissected the signaling events underlying this effect and found that CD28 T195P, but not RHOA G17V, enhanced the phosphorylation of key TCR signaling molecules, suggesting that RHOA G17V modulates NFAT transcriptional activity through a distinct mechanism. By co-immunoprecipitation experiments, we identified the histone acetyltransferase p300 as a major interacting partner of RHOA G17V. p300 inhibition abolished the increased IL-2 secretion induced by CD3/CD28 stimulation in cells expressing RHOA G17V and/or CD28 T195P. Chromatin immunoprecipitations revealed an increase of p300-specific H3K18ac and H3K27ac marks at the IL-2 promoter, and immunofluorescence staining revealed an increase of these marks at the whole genome level in cells harboring the RHOA G17V mutant. Finally, immunofluorescence staining of tumor samples from four AITL patients harboring RHOA G17V showed that neoplastic TFH (T Follicular Helper cell) cells had increased H3K18ac and H3K27ac levels compared to non-neoplastic T cells. Conclusions: Collectively, these findings reveal an unexpected role for RHOA G17V in potentiating CD28 T195P-induced NFAT transcriptional activity through the modulation of p300 HAT activity and expand the notion that epigenetic deregulation contributes to the pathogenesis of TFH lymphomas. Our results suggest that targeting p300 acetyltransferase activity may open new avenues for TFH lymphoma therapies. Keywords: follicular helper T-cell (TFH) lymphoma, epigenetics, T-cell activation, RHOA G17V, p300 TCL-423 The Outcomes of Patients With T‑Cell Prolymphocytic Leukemia After Allogenic Stem Cell Transplant: A Multicenter Retrospective Study Mwanasha Merrill MD1, Robert Redd MS1, Shambhavi Singh MD PhD2, Akil Vicks BS1, Vincent Ho MD1, Amar Kelkar MD1, Salvia Jain MD2, Eric Jacobsen MD1 1Dana Farber Cancer Institute, Boston, USA. 2Massachusetts General Hospital, Boston, USA Context: T-cell prolymphocytic leukemia (T-PLL) is an aggressive and rare T-cell malignancy with limited data reporting patient outcomes. Allogeneic transplant (allo-HCT) is the only option for cure. Objective: We aim to report the treatment patterns and outcomes of T-PLL patients after allo-HCT from two centers in the United States. Design: We conducted a retrospective analysis of patients diagnosed with T-PLL who underwent allo-HCT between 2002-2022 at Dana Farber Cancer Institute and Massachusetts General Hospital. Time-to-event endpoints are estimated using the Kaplan-Meier method with 95% confidence intervals calculated using Greenwood’s method to estimate variance. Results: Thirtyfive patients were identified with a median age of 61 (range 41-77). The Karnofsky performance status was >90 for 49% of the patients (range 70-100%). The median number of transplants was 1 (range 1-2). Frontline therapies included: alemtuzumab (74%), fludarabine (11%), pentostatin (3%), and unknown (11%). The majority of patients (66%) received an unrelated donor allo-HCT. The most used conditioning regimen was busulfan and fludarabine (66% of patients). The most common GVHD regimen in 31% of the patients was methotrexate, sirolimus, and tacrolimus. The median follow-up was 60.8 months. Of the patients with graft versus host disease, 46% had acute GVHD (aGVHD), while 37% had chronic GVHD (cGVHD). Of the patients with aGVHD, 56% had grade 2, and 19% had grade 3. There were no grade 4 events. The patients who experienced cGVHD mostly had mild symptoms (69%). There was no severe cGVHD. The median time to max grade was 3.4 months for aGCVD and 12.7 months for cGVHD. The median overall and progression-free survival were 24.0 and 21.1 months, respectively. The most common causes of death were disease progression (40%) and infections (11%). At 72 months, the probability of non-relapse mortality in the patients with vs without GVHD was 0.44 (0.180.71) vs 0.7 (0.3-1.11), and the transplant-related mortality (TRM) was 0.19 (0.02-0.37) vs 0.08 (0-0.23). This was not statistically significant. Conclusion: The outcomes of T-PLL patients remain dismal despite allo-HCT, with relapse still being the most common cause of treatment failure. Novel therapies are needed for this rare and aggressive disease. Keywords: TCL, T-PLL, allogeneic transplant, outcomes
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