PIM1 mutation

In conclusion, both BCL6-R-positive FL and BCL6-R-positive DLBCL had a common mutational profile; but also, differences. DLBCL cases had a higher density of microenvironment markers.

The multivariate analysis observed the association between high lactate dehydrogenase value and the immunohistochemical expression of PIM1 or with the mutant status of the PIM1 gene representing negative prognostic factors (HR = 2.066, P = .042, respectively HR = 3.100, P = .004). In conclusion, our preliminary data suggest that the oncogenic mutations of PIM1 and MYD88 in our DLBCL cohort may improve the diagnosis and prognosis of DLBCL patients in an advanced stage.

Our empirical observations demonstrated that the combination of zanubrutinib with HD-MTX yielded a marked clinical response and tolerability among newly diagnosed PCNSL patients. Non-invasive CSF liquid biopsy profiling may be feasible for evaluating treatment response and tumor burden.

PTL may benefit from HD-MTX in preventing relapse, while alternative treatments should be explored for DLBCL-T. Future studies should consider PTL and DLBCL-T as separate entities to better understand their characteristics and optimize treatment strategies.

The current findings reveal the clinicopathologic and genetic features of HT-MZLs, suggesting that these tumors might constitute a group distinct from MZL and de novo non-GCB type DLBCL. TBL1XR1 mutations may be considered a predictor of HT in MZL.

The novel induction treatment of MIT achieved encouraging responses in newly diagnosed PCNSL patients with acceptable toxicities. The early clearance of ctDNA in CSF may be related to favorable survival.

PIM1 mutations did not affect the proliferation of DLBCL cells and did not increase resistance to doxorubicin, excluding the proliferation rate or treatment resistance as a cause of the poor prognosis associated with PIM1 mutations...Finally, in transwell assays, PIM1 mutant cells exhibited markedly increased migratory potential. Taken together, these studies indicate that PIM1 mutants are not likely associated with differential drug responses, but rather facilitate tumor dissemination and are thus associated with inferior prognosis in DLBCL patients harboring PIM1 mutations.

Our report represents one of the most extensive and detailed studies regarding the landscape of BCL11B point and indel mutations in human cancer. BCL11B alterations occur widely in mature, immature, B-cell, Tcell, and sarcomatous malignancies. TP53, PIM1, and SOCS1 are the most commonly co-mutated genes.

Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Finally, the relapsed lymphoma cells showed in vitro resistance to standard BTK inhibitors but sensitivity to vecabrutinib, active against mutated BTK, and to PIM1 inhibitor. In summary, we provide in-depth molecular characterization of a case representing leukemic form of DLBCL and discuss mechanisms that may have contributed to lymphoma progression and development of drug resistance.

The identification of specific mutations in each subgroup, which were largely consistent with previous studies, indicates that the LymphGen classifier may be valuable in individualized treatment approaches for DLBCL patients. Additionally, this study demonstrates that unclassified group ("Other") may potentially be established as a distinct subgroup.

In addition to the proposals already made concerning the CLL cell of origin, our study highlights that analysis of IGH recombinatory activity can identify CLL cases from different origins. Finally, on-going Sμ-3'RRrec in Sμ-3'RRrecHigh cells appeared to presumably be the consequence of high c-MYC expression, as c-MYC overexpression potentiated IGH rearrangements and Sμ-3'RRrec, even in the absence of AID for the latter.

In this study we identified modulators of the response to the PI3K-alpha-specific inhibitor, BYL719, in PIK3CA mutant GCs...Our data provide clear mechanistic insights into PI3K-alpha inhibitor response in PIK3CA mutant gastric tumors and can inform future work as mutant selective inhibitors are in development for diverse tumor types. Implications: Loss of either NEDD9 or BCL-XL confers hyper-sensitivity to PI3K-alpha inhibition while loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.

Our findings demonstrate that AID interacts with either DNMT1 or TET2 to form a complex to bind with a PIM1 promoter and thus is responsible for the modulation of PIM1 expression. These results provide insights into an alternative role of AID to DLBCL-associated genes.

In our study, treatment with orchiectomy, six cycles of immunochemotherapy, and contralateral RT was effective. However, because CNS prophylaxis is an essential part of testicular DLBCL management, better treatment strategies than intrathecal therapy are required.

The findings of this study indicate that DLBCL patients with MYD88 and MYD88 are likely to be two subgroups with different clinical and molecular characteristics. The survival of patients with MYD88 is not superior than those with MYD88, even poorer when focusing on the non-GCB subtype.

In conclusion, we identified three molecular subtypes of DEL, unveiled distinct genetic, transcriptional, and microenvironmental properties, and highlighted epigenetic therapeutic approaches for targeting histone acetylation in DEL.

Finally, we established the functional consequences of mutations by means of protein modeling (CD79B, PLCG2, PIM1, MCL1 and IRF8). These data expand the knowledge on the genomics behind the heterogeneous FL population and, upon replication in larger cohorts, could contribute to risk stratification and the development of targeted therapies.

PIM1, SGK1, BTG2, FAS, MYC, and MYD88 were common mutations in pancreatic DLBCL. PIM1 and MYD88 mutations indicated worse prognosis.

Our study demonstrates that ibrutinib-based therapy is effective and relatively safe for the treatment of r/r CNSL. Patients with less genomic complexity, especially with regard to TMB, might benefit more from ibrutinib regimens.

In patients with DEL, the overall response rate of R-EPOCH regimen was higher than that of RCHOP or RCHOP-like regimen (81.5% vs 63.4%, P=0.004) . DEL is a group of aggressive lymphomas with relatively poor PFS. The R-EPOCH regimen may improve the overall prognosis of patients.

90% of patients received systemic chemotherapy for initial treatment, with 41% receiving high dose Methotrexate, Rituximab and Temozolomide... We identified highly recurrent genetic alterations in PCNSL. Our data suggest that some heterogeneity in the most frequent mutations in PCNSL may be related to ethnicity. Hispanic patients in our study have better 2-year OS; however, the data is limited by the retrospective analysis and the small patient number.

We present here a refined classification of DLBCL genetic subgroups that combines previously described classification algorithms and extends it to allow classification of more tumors into additional subgroups that preserve the major divisions of existing systems. This represents an important advancement that will facilitate further understanding of genomic complexity in this disease.

Our results confirm the relevance of mutations in B-cell receptor/nuclear factor-κB signaling and immune escape pathways in IVLBCL and identify novel driver alterations. The similar mutational profile in tumors with extravascular dissemination suggests that these cases may also be considered in the spectrum of IVLBCL.

Overall survival (OS) was calculated from the start of temozolomide (TMZ) or tissue collection to last contact using insurance claims data... When compared to non-CNS lymphomas, PCNSL tumors showed significantly higher mutation rates in MYD88 (70% vs. 7%) , PIM-1 (58% vs. 7%) , CD79B (42% vs.

The progression-free survival (PFS) in patients with DLBCL with MYD88 non-L265P mutation was statistically better than in patients with MYD88 L265P mutation. The interpretation of variants of MYD88 mutation offers a precise guide for the management of DLBCL.

These high-mutant genes detected in PBL indicated a tendency to shorten overall survival (OS) and progression-free survival (PFS), which may lead to poor prognosis. Furthermore, the nuclear factor kappa-B (NF-κB) pathway and related regulatory factors are essential for the development of targeted therapy as well.

Such fact can be exploited to reconstruct chromosomal disruptions in individual cells using scRNAseq and to uncover the subclonal architecture of the disease. Grants: MH-CZ_AZV_NU20-08-00314, MH-CZ_AZV_NV19-03-00091, MEYS-CZ_MUNI/A/1330/2021, MH-CZ_RVO_65269705.

Older DLBCL also manifested reduction in CD4 naïve T and CD8 naïve T cells, and also increased recruitment of exhausted T cells and macrophages, leading to immunosuppressive tumor microenvironment. Our work thus contributes to the understanding of aging-related oncogenic mutations and tumor microenvironment alterations in lymphoma progression, and may provide new insights to mechanism-based targeted therapy in DLBCL.

Finally, we constructed an OS predict model of PT-DLBCL patients using above factors with a high accuracy. In conclusion, our results revealed genomic characterization of PT-DLBCL, and the mutation of BTG2 was an independent factor predicting a poor prognosis.

We developed a new molecular classification to divide CNS DLBCL into CDP and non-CDP groups based on CD79B and PIM1 mutational status. Patients with PIM1 and/or CD79B mutations had favorable long-term survival after high-dose methotrexate-based polychemotherapy.

MD results indicate significant conformational altercations in the structure of PIM1, especially upon F147C mutation. This study provides a significant insight into the PIM1 dysfunction upon single amino acid substitutions, which can be utilized to get insights into the molecular basis of PIM1-associated disease progression.

The molecular characteristics of CD5+ DLBCL are unique. MYD88, PIM1 and KMT2D were the most common mutations and 50% cases could be classified into MCD subtype. Identifying the genetic traits of CD5+ DLBCL is helpful for deeply understanding the pathogenesis and for further target therapy developing of this DLBCL subgroup.

We developed a new molecular methodology to divide CNS DLBCL into CDP and non-CDP groups based on CD79b and PIM1 mutational status. Patients without PIM1 and CD79b mutations had unfavorable long-term survival after HD-MTX-based polychemotherapy, and the potential molecular mechanism awaits further investigation.

We further found that compared to patients with low-risk score, patients with high-risk score had higher sensitivity to some drugs of targeting the immune microenvironment, including TGFβ receptor inhibitors SB525334 ( P <0.0001) and SB505124 ( P <0.0001) and immunomodulator Lenalidomide ( P =0.041), as well as NF-κB inhibitors Parthenolide ( P <0.0001) and TPCA-1 ( P <0.0001) and JAK inhibitors Ruxolitinib ( P =0.014) and TG101348 ( P =0.0053), accompanying with significantly lower IC50 values. In addition, another common chemotherapeutic drug Gemcitabine was also predicted to be more sensitive for patients with high-risk score ( P =0.047). Other targeted drugs such as Aurora kinase inhibitors VX-680 ( P <0.0001) and ZM-447439 ( P =0.014), Bcl-2 inhibitors Obatoclax Mesylate ( P =0.00036) and Navitoclax ( P <0.0001), and CDK inhibitors Roscovitine ( P =0.0012), AT-7519 ( P =0.0033), PHA-793887 ( P <0.0001) and THZ2-49 ( P =0.0053) also exhibited higher drug sensitivity for patients with high-risk score. Conclusions : PIM1 mutations play a vital role in patient risk stratification and provide novel insights into therapeutic decision making for DLBCL patients with high-risk score.