Feldman, Andrew L.

ABSTRACTNodal follicular helper T‐cell (T FH) lymphoma of the angioimmunoblastic (AITL) subtype has a dismal prognosis. Using whole‐exome sequencing (n = 124), transcriptomic (n = 78), and methylation (n = 40) analysis, we identified recurrent mutations in known epigenetic drivers (TET2, DNMT3A, IDH2 R172 ) and novel ones (TET3, KMT2D). TET2, IDH2 R172 , DNMT3A co‐mutated AITLs had poor prognosis (p < 0.0001). Genes regulating T‐cell receptor (TCR) signaling (CD28, PLCG1, VAV1, FYN) or activation (RHOA G17V ) or regulators of the PI3K‐pathway (PIK(3)C members, PTEN, PHLPP1, PHLPP2) were mutated. CD28 mutation/fusion was associated with poor prognosis (p = 0.02). WES of purified, neoplastic T‐cell (CD3+PD1+) demonstrated high concordance with whole tumor biopsies and validated the presence of TET2 and DNMT3A in tumor and non‐lymphoid cells, but other mutations (CD28, RHOA G17V , IDH2 R172 , PLCG1) in neoplastic cells. Integrated DNA‐methylation and mRNA expression analysis revealed epigenetic alterations in genes regulating TCR, cytokines, PI3K‐signaling, and apoptosis. RNA‐seq analysis identified fusion transcripts regulating TCR‐activation (8%), revealed a restricted TCR‐repertoire (α = 87%, β = 72%), and showed the presence of Epstein–Barr virus transcriptome (73%). GEP demonstrated the association of B‐cells or dendritic cells in the tumor milieu with prognosis (p < 0.01). RNA‐seq and WES analysis of 12 AITL‐patient‐derived‐xenografts (PDX) showed that bi‐allelic TET2 and DNMT3A mutations or sub‐clonal mutations (PLCG1, PHLPP2) propagated in sequential passages, and gene signatures related to T FH and T CM (central‐memory) were well‐maintained through passages. Gene expression signatures associated with late PDX passages (3rd–5th) were enriched with proliferation and metabolic reprogramming‐related genes and predicted prognosis in an independent AITL series. Low PHLPP2 mRNA expression predicted poor prognosis (p = 0.05) and engineered PHLPP2 or TET2 loss in CD4+ T‐cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.

Abstract Family history of hematologic malignancy (FHHM) is an established risk factor for developing lymphoma, but studies examining associations between self-reported FHHM and lymphoma prognosis during the recent treatment era are limited. Utilizing a prospective cohort study, we evaluated associations between FHHM and prognosis for common lymphoma subtypes, including diffuse large B-cell (DLBCL), follicular (FL), marginal zone (MZL), mantle cell (MCL), Hodgkin (HL), and T-cell (TCL) lymphomas. We used the Mayo Clinic component of the Molecular Epidemiology Resource, a prospective cohort study of newly diagnosed lymphoma patients enrolled from 2002 to 2015. Self-reported FHHM (HL, NHL, leukemia, or multiple myeloma) in a first-degree relative was obtained via questionnaire. Primary outcomes were overall survival (OS) and event-free survival (EFS; time from diagnosis to disease progression, initiation of second-line therapy, or all-cause death). Secondary outcomes were failure to achieve 24 months of event-free survival (EFS24; associated with aggressive disease and poor outcomes) and lymphoma-specific survival (LSS; time from diagnosis to death from lymphoma or lymphoma treatment-related complications). We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of FHHM with OS, EFS, and LSS, and logistic regression to estimate odds ratios (ORs) and 95% CI for the association with failure to achieve EFS24. All models were adjusted for sex and a lymphoma subtype specific prognostic index. The cohort consisted of 650 DLBCL, 679 FL, 291 MZL, 178 MCL, 254 HL, and 196 TCL patients. The prevalence of FHHM ranged from 9.7% in TCL to 14% in FL. FHHM was not associated with OS in any subtype, but MCL patients with FHHM showed an inferior EFS (HR=1.70, 95% CI 1.02-2.85; p=0.04). For EFS24, FHHM was associated with failure to achieve EFS24 only in FL (OR=1.57, 95% CI 0.99-2.48; p=0.05). Similarly, FHHM was associated with inferior LSS in FL patients (HR=1.98, 95% CI 1.11-3.53; p=0.02). In a treatment subgroup analysis of FL patients, the FHHM associations with failure to achieve EFS24 (OR=2.48, 95% CI 1.04-5.74; p=0.04) and inferior LSS (HR=2.68, 95% CI 1.09-6.58; p=0.03) strengthened among those treated with frontline immunochemotherapy (IC). In summary, there were no evidence of associations between FHHM and OS across lymphoma subtypes, but MCL patients with FHHM displayed inferior EFS. FL patients with FHHM were more likely to not achieve EFS24 and to ultimately die of their lymphoma or a lymphoma treatment-related complication. This finding was stronger in more aggressive FL requiring frontline IC. This novel finding would suggest that genetic or environmental factors associated with FHHM may underlie pathways that impact disease aggressiveness and early clinical failure in FL. Citation Format: George Cholack, Raphael Mwangi, Thomas M. Habermann, Verena Hinder, Rosalie Griffen, Dennis Robinson, Andrew L. Feldman, Thomas E. Witzig, Stephen M. Ansell, Brian K. Link, Yucai Wang, Carrie A. Thompson, Susan L. Slager, Matthew Maurer, Anne J. Novak, James R. Cerhan. Family history of hematologic malignancy and prognosis across lymphoma subtypes: Novel association with poor outcomes in follicular lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7344.

ABSTRACTBackgroundPrimary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP) are indolent CD30‐positive lymphoproliferative disorders that rarely express TCR‐γδ. However, primary cutaneous gamma‐delta T‐cell lymphoma (pcGDTCL), characterized by TCR‐γδ expression on neoplastic cells, is a rare, aggressive cutaneous T‐cell lymphoma with a poor prognosis. Accurate differentiation is essential due to distinct clinical behavior and treatment.MethodsWe identified 11 TCR‐γδ‐positive pcALCL cases from internal and consultation files, verified by two cutaneous lymphoma experts, with clinicopathologic data recorded.ResultsThe median age was 68 years (range 38–95). Most cases presented as a single dermal lesion on the upper extremities. All were ALK‐negative, CD30‐positive (> 90% tumor cells), TCR‐βF1‐negative, and diffusely TCR‐γδ‐positive. CD4−/CD8− (54.5%) and CD4+/CD8− (45.5%) immunophenotypes were observed. CD2 (63.6%) and CD3 (54.5%) were the most common T‐cell antigens. Ulceration, inflammation (both 45.5%), and necrosis (36.4%) were frequent. Angiotropism, angiocentricity, and myxoid stroma appeared in one case; epidermotropism in two. Four of ten tested were DUSP22‐rearranged, and TP63 was negative in all eight tested.ConclusionsMost ALK‐negative TCR‐γδ‐positive pcALCL were CD4−/CD8−, followed by CD4+/CD8−. DUSP22 rearrangement occurred in 40% of cases, similar to reports in typical pcALCL. Its prognosis and the role of DUSP22 are yet to be clarified.

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is clinically heterogeneous, and gene expression profiling has identified at least two biologically distinct DLBCL subtypes defined by their cell of origin (COO): germinal center B cell (GCB) and activate B cell (ABC) or non-GCB. We evaluated a variety of putative DLBCL risk factors for etiologic heterogeneity by the COO in a clinic-based study of newly diagnosed DLBCL cases (N = 638) and frequency-matched controls (N = 2,253). Methods: The COO was determined on formalin-fixed, paraffin-embedded tumor tissue, with DLBCL classified as GCB (N = 283), non-GCB (N = 188), or undetermined/missing (N = 167; mainly because of lack of tissue). Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: We identified heterogeneity by the COO for low socioeconomic status (SES), which was only associated with non-GCB DLBCL (OR = 1.88 for low vs. average SES; 95% CI, 1.08–3.27); alcohol use, which was only associated with GCB DLBCL (OR = 0.48 for former drinkers; 95% CI, 0.29–0.80 and OR = 0.47 for current drinkers; 95% CI, 0.32–0.71); and borderline heterogeneity for the regular use of regular/extra-strength aspirin, which was only associated with non-GCB DLBCL (OR = 0.36; 95% CI, 0.16–0.85). In contrast, there was no significant heterogeneity by the COO for family history, medical history, or other lifestyle factors. Conclusions: Although requiring confirmation, most risk factors for DLBCL did not show etiologic heterogeneity by the COO, with some notable exceptions including alcohol use, SES, and perhaps regular use of regular/extra-strength aspirin showing associations. Impact: Mechanistically, these findings suggest that most of the DLBCL risk factors evaluated here influence lymphomagenesis prior to differentiation into COO subtypes, with selected factors acting later.

Background: Positron emission tomography (PET) scan is the imaging modality of choice for initial staging and response assessment of follicular lymphoma (FL). Quantitative parameters such as standardized uptake value (SUV) have been investigated as putative prognosticators in FL, with high baseline SUVmax predicting aggressive disease. To date, there is no data to guide treatment choices in patients (pts) with high SUVmax but with no documented evidence of histologic transformation (HT). Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, are more beneficial than R-Bendamustine (BR) in these pts. Therefore, we aimed to compare the efficacy of frontline R-CHOP and BR in newly diagnosed FL pts based on the SUVmax at baseline PET (bPET). Patients and Methods: Pts with newly diagnosed, biopsy-proven FL1-2 and FL3A who had a bPET scan and who received either first-line R-CHOP or BR within 6 months of diagnosis between 2002 and 2022 were evaluated. Analysis was restricted to pts with age &lt; 70 years to reduce confounding of age with treatment selection. Cohorts included were the FOLL12 (n=562, Luminari et al JCO 2022) and the R-chemotherapy arm of the RELEVANCE (n=216, Morschhauser et al NEJM 2018) clinical trials, the prospectively enrolled Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts (n=288) and a retrospective cohort from 13 Australian centers (n=219). Choice of chemotherapy regimen was per treating physician. Maintenance was per protocol (FOLL12/RELEVANCE) or per treating physician (MER/LEO/Australia). Event-free survival (EFS) and overall survival (OS) were defined as time from treatment initiation to progression, relapse, retreatment or death; both were censored at 72 months due to varying follow-up across cohorts. SUVmax was grouped by tertile within each cohort to account for potential differences in SUVmax distributions and patient populations across cohorts. Kaplan Meier curves and multivariable Cox models cohort-stratified and adjusted for clinical factors (FLIPI, ECOG PS, age, grade 3A) were used to evaluate outcomes. Results: The median age at diagnosis was 57 years (IQR 49-64). 651 (51%) pts were treated with R-CHOP and 634 (49%) with BR. Within the study cohorts, there was a prevalence of cases receiving BR compared to R-CHOP in the Australian (90% vs 10%) and MER/LEO (68% vs 32%) cohorts, while the opposite was observed in the RELEVANCE (16% vs 84%) and FOLL12 (37% vs 63; p&lt;0.001) trials. Pts receiving R-CHOP were slightly younger (median 56 vs 58 years, p=0.005), more frequently had grade 3A (17% vs 7%, p&lt;0.001), elevated LDH (27% vs 22%, p=0.029), bulky disease &gt; 7 cm (44% vs 37%, p=0.019), lower ECOG PS (PS &gt;1 7% vs 13%, p&lt;0.001), and higher rate of high risk FLIPI (37% vs 30%, p=0.005). Baseline SUVmax was slightly lower in R-CHOP (median 10.7, IQR 7.9-14.9) vs BR (median 11.0, IQR 8.2-14.2) treated pts (p=0.0045). At a median follow-up of 56 months (range, 1-72 months), 415 pts (32%) had an event and 103 (8%) died. Higher SUVmax was not associated with EFS (middle tertile HR=0.96, 95% CI 0.76-1.22; upper tertile HR=0.86, 95% CI 0.68-1.09; p=0.45) or OS (middle tertile HR=1.28, 95% CI 0.80-2.05; upper tertile HR=0.97, 95% CI 0.59-1.59; p=0.44) in multivariable models stratified on cohort and adjusted for treatment and clinical factors. We then compared outcomes by treatment within tertiles of SUVmax. In multivariable models, R-CHOP had modestly inferior EFS to BR in low (HR=1.27, 95% CI 0.84-1.93) and middle tertiles (HR=1.49, 95% CI 0.99-2.25), and modestly superior OS to BR in low (HR=0.59, 95% CI 0.23-1.47) and middle (HR=0.79, 95% CI 0.37-1.71) tertiles. Both EFS (HR=1.06, 95% CI 0.71-1.58) and OS (HR=1.02, 95% CI 0.45-2.30) for R-CHOP were similar to BR in the highest tertile. No comparisons identified a statistically significant benefit for either therapy in multivariable models when evaluating SUVmax tertile subsets. Conclusions: In this large multicenter study of newly diagnosed FL pts with bPET who received frontline immunochemotherapy, higher baseline SUVmax was not associated with inferior outcomes after adjusting for treatment and clinical factors. Within the caveats of retrospective studies and confounding of treatment selection, these data provide no clear insights for SUVmax-based therapy selection in first-line follicular lymphoma pts treated with immunochemotherapy.

Introduction: Patients with non-Hodgkin Lymphoma (NHL), especially adolescents and young adults, can face late effects from treatment, including decreased fertility. Due to time constraints prior to treatment initiation and sometimes financial limitations, implementing fertility counseling and referral-based guideline care remains challenging. We aim to understand the occurrence and predictors of fertility counseling and preservation in patients with NHL in the Lymphoma Epidemiology of Outcomes (LEO) cohort study. Methods: The LEO cohort prospectively enrolled newly diagnosed patients with NHL from 2015-2020 at 8 academic medical centers in the US. Clinical. Treatment data were abstracted from medical records, pathology was reviewed and classified by a LEO pathologist, and participants completed a self-administered questionnaire. Participants were then prospectively followed to identify outcomes and collect additional patient reported data, including a survivorship questionnaire at follow-up 3 years (FU3) after diagnosis that included items on fertility counseling and preservation. The questionnaire contained two fertility questions analyzed: whether healthcare providers discussed the impact of lymphoma treatment on fertility, and whether providers discussed the process of fertility preservation. This analysis was based on participants aged 18-50 years at enrollment and who completed the fertility questions at FU3. Women who had undergone natural or procedural menopause and men who had undergone vasectomy pre-treatment were excluded. We estimated the association of demographic and clinical factors with fertility preservation using odds ratios (ORs) and 95% confidence intervals (CI) from univariate and multivariable logistic regression models. Results: Seventy-seven patients were included in the analysis: 36 females (46%) and 41 males (53%). The median age of diagnosis was 40 years (IQR 30-45), and 36 (47%) participants were in the age 18-39-year category. Participant self-identified race/ethnicity was 69% non-Hispanic White, 22% Hispanic, 4% Black and 3% Asian. Sixty (78%) patients were treated with alkylators, 12 (15.6%) with non-alkylators, and 5 (6.5%) with radiation. Fifty-five (71%) of the patients were classified as having aggressive lymphoma, with follicular, extranodal marginal zone, primary cutaneous follicle center, and nodal marginal zone B-cell lymphoma defined as indolent and remaining subtypes aggressive. Around 6% of female patients underwent fertility preservation after lymphoma diagnosis, compared to 12.2% of male patients. All the patients who had undergone fertility preservation after lymphoma diagnosis were in the 18-39-year age group. On univariate analysis, females were more likely to have undergone fertility toxicity and preservation discussions compared to males, with 72% of females and 59% of males recalling a discussion regarding fertility (OR 1.8, 95% CI 0.7-4.9, p=0.21). Those age 18-39 were significantly more likely to have undergone fertility discussion compared to those aged 40-50 (OR 10.2, 95% CI 3.3-39.2, p&lt;0.001). Patients treated with alkylating therapy were significantly more likely to undergo fertility discussion when compared to those on non-alkylating therapy (OR 9.0, 95% CI 2.3-45.5, p&lt;0.01). In addition, 75% of those with aggressive lymphoma compared to 41% of patients with indolent lymphoma had fertility discussion (OR 4.2, 95% CI 1.5-12.4, p=0.01). White patients were significantly less likely than Hispanic, Black and Asian patients to have fertility discussion (OR 0.2, 95% CI 0.04-0.6, p&lt;0.01). In the multivariable analysis, alkylating therapy (OR 8.9, 95% CI 1.6-66.7) and age 18-39 years (OR 10.9, 95% CI 2.9-55.3) remained significant predictors of fertility discussion; White race was also trending towards significance (OR 0.2, 95% CI 0.04-1.0, p=0.08). Aggressive lymphoma subtype was not a significant predictor of fertility discussion. Conclusions: In this cohort of lymphoma survivors 3 years post-diagnosis, we found that Hispanic patients, those diagnosed at a younger age and exposed to alkylating chemotherapy agents were significantly more likely to undergo discussions regarding the effects of lymphoma treatment on fertility. Our study highlights the importance of all cancer patients of childbearing age having the opportunity to address fertility concerns during clinic visits.

Background: The Optimized Hemophagocytic Lymphohistiocytosis (HLH) Inflammatory (OHI, Zoref-Lorenz et al, Blood, 2022) index, defined by the combined elevation in serum soluble CD25 (sCD25) and ferritin, has emerged as a promising prognostic tool for patients with newly diagnosed hematologic malignancies, demonstrating superior performance in predicting 500-day mortality compared to HLH-2004 criteria. However, previous studies were retrospective, with a substantial proportion (65%) of patients suspected clinically to have HLH. We evaluated the performance of the OHI index in an unselected, prospective cohort of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. Methods: We analyzed the predictive utility of the OHI index in 331 newly diagnosed DLBCL patients enrolled from 2002-2015 in the prospective Iowa/Mayo Molecular Epidemiology Resource cohort. Ferritin and sCD25 levels were quantified in pre-treatment serum samples using R&D ELISA kits. OHI values were also optimized based on 500-day mortality in the cohort using receiver operating curve analysis with internal validation. Patients were classified as OHI+ using the original and newly optimized thresholds for sCD25 and ferritin. The primary endpoint was 500-day survival, and the secondary endpoints were event-free survival (EFS) at 24 months (EFS24), EFS, and overall survival (OS). The predictive capability of the OHI index was evaluated using logistic regression to determine odds ratios (OR) and 95% confidence intervals (CI) for 500-day mortality and EFS24, as well as Cox regression to calculate hazard ratios (HR) and 95% CIs for EFS and OS. Results: The median age at diagnosis of the 331 patients was 63.5 years (interquartile range, 54.5-74), and 168 (51%) were male. Using the original thresholds (sCD25 3,900 U/mL and ferritin 1,000 ng/mL), 4.2% of patients were OHI+, with a more than 5-fold higher 500-day mortality risk compared to OHI- patients (OR=5.6; CI 1.6-17, p&lt;0.001). After optimizing thresholds for sCD25 (2,400 U/mL) and ferritin (250 ng/mL) to predict 500-day mortality, 23.6% were OHI+ and the OHI+ group had a 9-fold higher 500-day mortality risk (OR=9.2; CI 4.0-24, p&lt;0.001), with 31% mortality in the OHI+ vs 5% in the OHI- group. OHI+ patients exhibited more B-symptoms (35% vs 20%, p=0.027), elevated LDH levels (76% vs 34%, p&lt;0.001), poorer performance status (Eastern Cooperative Oncology Group 2+: 38% vs 12%, p&lt;0.001), and more advanced stage disease (Stage IV: 57% vs 38%, p&lt;0.001), although the frequency of a high International Prognostic Index (IPI) was not statistically different between the groups (IPI 3-5: 44% vs 36%, p=0.28). After adjusting for age and IPI, OHI+ remained a strong predictor of 500-day mortality (OR=5.0; CI 1.9-13, p=0.001). Further adjustment for the cell of origin did not impact the results. The association of OHI+ status with 500-day mortality was similar in IPI 0-2 (OR=5.8; CI 1.2-29, p=0.033) and 3-5 (OR=6.8; CI 0.6-73, p=0.11). OHI+ patients were also more likely to not achieve EFS24 (45% vs 13%), with a 3-fold greater risk after adjusting for age and IPI (OR=3.2; CI 1.5-6.5, p=0.0018). The OHI index also retained its predictive ability over longer-term follow-up (median 9.8 years for living patients) for both OS (HR=2.0; CI 1.0-4.0, p=0.040) and EFS (HR=2.2; CI 1.1-4.3, p=0.030) after adjusting for age and IPI. Cytokine profiling using multiplex ELISA identified elevated inflammatory markers in OHI+ patients, underscoring the role of systemic inflammation in prognosis. The distribution of cytokines was significantly different between the groups, with consistently higher means in the OHI+ vs OHI- group, including IL1a (1,628 vs 759 pg/ml, p=0.008), CCL2 (1,020 vs 724 pg/ml, p=0.028), CXCL10 (165 vs 53 pg/ml, p&lt;0.0001), and CXCL9 (380 vs 150 pg/ml, p&lt;0.0001). Conclusions: While the original OHI index for prediction of 500-day mortality was validated in this unselected cohort of newly diagnosed DLBCL patients, optimization of the OHI thresholds identified a larger OHI+ group (24%), enhanced the identification of hyperinflammation, improved predictive ability for early (500-day) mortality, and predicted EFS24 status and long-term OS. This underscores the clinical relevance of the OHI index, supports the need to evaluate disease-specific thresholds, and suggests its potential for use in routine management and as enrollment criteria in clinical trials for novel therapies.

Introduction: Nodal lymphomas of T-follicular helper cells (n-TFHLs) are considered neoplasms of mature TFH cells and are classified by the World Health Organization (WHO) under one umbrella with three subtypes: angioimmunoblastic-type (n-TFHL-AI), nodal TFHL, follicular type (n-TFHL-F), and nodal TFHL, not otherwise specified (n-TFHL-NOS). TET2 mutations in n-TFHL-AI subtype frequently co-occur with IDH2R172 mutations. Methods: To elucidate the cooperative role of TET2 and IDH2R172K mutation in n-TFHL-AI pathogenesis, we generated a murine model with Tet2 loss and IDH2R172K knock-in mutation in CD4+ T cells (Tet2-/-/IDH2R172K) by crossing Tet2Flox/Flox/IDH2R172K mice with Cd4-Cre transgenic mice. This resulted in Tet2 exon 3 deletion and IDH2R172K knock-in mutation specifically in CD4+ T cells. Murine tumors were comprehensively evaluated through immunohistochemistry and flow cytometry. Transcriptomic (RNA-seq), 5-hydroxymethylcytosine (5hmC), and 5-methylcytosine (5mC) profiling, and genomic (whole exome sequencing [WES]) analyses were conducted on both earlier time points (preneoplastic) and neoplastic cells. Functional validation involved proliferation, T-cell polarization, and Western blotting assays. Results: The transcriptomic analysis (p &lt; 0.05) in n-TFHL-AI (double-mutant) cases showed enrichment of TFH-like signature, IL-12-signaling, NF-ΚB, and downregulation of TH1 cell differentiation (including IFNγ signaling). Evaluation of double-mutant mice revealed an earlier tumor onset than Tet2 mutant mice, with a median survival of 1.3 years compared to 1.7 years (p=0.006), respectively. With chronic stimulation by T cell-dependent antigens (sheep red blood cells [SRBCs]), these mice showed B-cell expansion with a 100% incidence of lymphoid neoplasms, in contrast to PBS-treated mice, where myeloid and lymphoid diseases occurred at an equal ratio. Genomic analysis of murine tumors revealed a unique mutation spectrum in metabolic genes (Ata3d3a, Atp1a3, Ppp4r3a, and Nemf), T- and B-cell interaction (Gnai3), Stat pathway (Jak1), and DNA repair (Zfp451). Transcriptomic analysis of tumors showed downregulation of Tbx21, increased TFH-related genes, and increased expression of Bcl6 with downregulation of its known suppressed genes. Transcriptomic analysis of murine CD4+ T cells isolated at 12 weeks revealed downregulation of genes associated with TH1-cell differentiation and Trp53 signaling, concurrent activation of T-cell receptor (TCR) and MAPK signaling, and API-complex. We demonstrated elevated levels of 2-hydroxyglutarate (2-HG) in double-mutant cells, and enasidenib (IDH2R172 inhibitor) treatment significantly decreased 2-HG levels and increased Tbx21 expression. Mutant cells showed a proliferative advantage in IL-2 and IL-21 in vitro conditions, resulting in enhanced TCR, AKT, ERK1/2, p-65, and inactivation of p-FOXO1 protein. While these cells showed a growth advantage in in vitro culturing with TFH conditions, their growth and polarization were impaired in TH1 conditions, indicating a differentiation block. Tet2-/-/IDH2R172K mice (12-week) with SRBCs treatment revealed a significant induction of B and CD4+ T- cell populations compared to wild-type (WT) mice (p=0.01). In vitro co-culturing experiments demonstrated that Tet2-/-/IDH2R172K mutant CD4+ T-cells confer a substantial proliferative advantage to B-cells (p=0.021). Notably, these double-mutant CD4+ T cells exhibited superior proliferation compared to WT CD4+ T-cells when co-cultured with B-cells isolated from WT or double mutant mice (p=0.004). When Tet2-/-/IDH2R172K neoplastic cells with whole tumor were allografted into NOD scid gamma (NSG) mice, lymphoma developed within three months, but also showed numerous B-cells in the TME. This suggests that the propagation of neoplastic T-cells likely require B cell help. Overall, the TFH program remained intact in transplanted cells, and a global decrease in 5hmC levels and an increase in 5mC levels were observed. Conclusion: Tet2-/-/IDH2R172K murine CD4+ T cells exhibited hyperactive TCR signaling, impaired DNA damage response, and NF-ΚB activation as key oncogenic transitions. Both in vitro co-culturing and the allografting of neoplastic Tet2-/-/IDH2R172K cells showed dependence on B-cells, suggesting that interrupting T- and B-cell interaction could be a therapeutic approach.