Primary Central Nervous System Lymphoma Tumor Biopsies Show Heterogeneity in Gene Expression Profiles, Genetic Subtypes, and in vitro Drug Sensitivity to Kinase Inhibitors.

Primary central nervous system lymphoma (PCNSL) is clinically challenging due to its location and small biopsy size, leading to a lack of comprehensive molecular and biologic description. We previously demonstrated that 91% of PCNSL belong to the activated B-cell-like (ABC) molecular subtype of diffuse large B-cell lymphoma (DLBCL). Here we investigated the expression of 739 cancer related genes in HIV (-) patients using NanoString digital gene expression profiling in 25 ABC-PCNSL and 43 ABC-systemic DLBCL, all tumors were EBV (-).

Measurable Residual Disease in Mantle Cell Lymphoma: The Unbearable Lightness of Being Undetectable.

Purpose Of Review: This paper evaluates the benefits and limitations of detecting measurable residual disease (MRD) in mantle cell lymphoma (MCL) and assesses its prognostic value. It also aims to highlight the importance of detecting low MRD levels post-treatment and their application in clinical practice.

Recent Findings: Recent studies show that MRD levels predict relapse and survival outcomes in hematologic neoplasms, including MCL.

Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of neoplasms, with many cases remaining unclassifiable and categorized as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated 2 prognostic subtypes within PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including T follicular helper [T] biomarkers), and GEP analyses, separating them into PTCL-NOS (n = 63) and PTCL-TFH (also known as nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n = 38).

CDK8/19 inhibition triggers a switch from mitosis to endomitosis in cord blood megakaryocytes.

Neonatal and adult megakaryocytes differ in proliferative capacity and ploidy levels, and neonatal and adult platelets differ in function, gene expression, and protein content. The mechanisms underlying these differences are incompletely understood. CDK8 and CDK19 are transcriptional kinases part of the CDK-mediator complex, which regulates gene transcription in a cell-specific manner.

DEK regulates B-cell proliferative capacity and is associated with aggressive disease in low-grade B-cell lymphomas.

This study sheds light on the pivotal role of the oncoprotein DEK in B-cell lymphoma. We reveal DEK expression correlates with increased tumor proliferation and inferior overall survival in cases diagnosed with low-grade B-cell lymphoma (LGBCL). We also found significant correlation between DEK expression and copy number alterations in LGBCL tumors, highlighting a novel mechanism of LGBCL pathogenesis that warrants additional exploration.

Motive and opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements (an LLMPP study).

Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated.

Follicular lymphoma B cells exhibit heterogeneous transcriptional states with associated somatic alterations and tumor microenvironments.

Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma of germinal center origin, which presents with significant biologic and clinical heterogeneity. Using RNA-seq on B cells sorted from 87 FL biopsies, combined with machine-learning approaches, we identify 3 transcriptional states that divide the biological ontology of FL B cells into inflamed, proliferative, and chromatin-modifying states, with relationship to prior GC B cell phenotypes. When integrated with whole-exome sequencing and immune profiling, we find that each state was associated with a combination of mutations in chromatin modifiers, copy-number alterations to TNFAIP3, and T follicular helper cells (Tfh) cell interactions, or primarily by a microenvironment rich in activated T cells.

Navigating between Scylla and Charybdis: A roadmap to do better than Pola-RCHP in DLBCL.

In treating diffuse large B-cell lymphoma (DLBCL), oncologists have traditionally relied on the chemotherapy backbone of R-CHOP as standard of care. The two dangers that the hematologist must navigate between are the aggressive disease (Charybdis that in the absence of therapy systematically destroys all the ships) and the toxicity of the therapies (Scylla with its six monstrous heads that devours six crew members at a time), and hematologists have to navigate very carefully between both. Therefore, three different strategies were employed with the goal of improving cure rates: de-escalating regimens, escalating regimens, and replacement strategies.

Alport syndrome: A puzzling case of thrombocytopenia and giant unusual platelets in blood smear.

A puzzling case of thrombocytopenia and giant unusual platelets in blood smear reveals a past diagnosis of Alport syndrome in 44-year-old woman with end-stage renal disease and abnormal CBC values.

Mediastinal large B cell lymphoma and surrounding gray areas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Session 3 of the 2021 European Association for Haematopathology/Society for Hematopathology Workshop focused on mediastinal large B cell lymphomas and surrounding gray areas. One half of the session was dedicated to primary mediastinal large B cell lymphoma (PMBL) and included cases with classic clinicopathologic features, as well as cases with either morphologic or immunophenotypic variation, and PMBL-like cases with primary extramediastinal disease. The role of additional immunophenotyping and/or molecular testing to aid in the diagnosis of PMBL was discussed.

Subclonal TP53 mutations are frequent and predict resistance to radioimmunotherapy in follicular lymphoma.

Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in <5% of pretreatment follicular lymphoma (FL) specimens. We assayed archival follicular B-cell non-Hodgkin lymphoma specimens from a completed clinical trial, Southwest Oncology Group S0016, a phase 3 randomized intergroup trial of CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone) chemotherapy plus R-CHOP (rituximab-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radioimmunotherapy [RIT]-CHOP). Subclonal TP53 mutations (median allele frequency 0.

Molecular classification and identification of an aggressive signature in low-grade B-cell lymphomas.

Non-follicular low-grade B-cell lymphomas (LGBCL) are biologically diverse entities that share clinical and histologic features that make definitive pathologic categorization challenging. While most patients with LGBCL have an indolent course, some experience aggressive disease, highlighting additional heterogeneity across these subtypes. To investigate the potential for shared biology across subtypes, we performed RNA sequencing and applied machine learning approaches that identified five clusters of patients that grouped independently of subtype.

Transformation of FL into DLBCL with a PMBL gene expression signature.

We investigated the clinicopathologic features of 5 follicular lymphomas (FLs) that transformed (tFL) morphologically to diffuse large B-cell lymphomas (DLBCLs) and had a primary mediastinal large B-cell lymphoma (PMBL)-like gene expression profile (tFL-PMBLsig-pos). None of the tFL-PMBLsig-pos cases arose in the mediastinum, all cases tested had a germinal center B-cell phenotype, 20% were CD30+, 60% CD23+, 80% MAL+, 20% CD200+, and 0% CD273/PDL2+. Whole-exome sequencing detected alterations in genes associated with both FL/DLBCL (CREBBP, KMT2C, KMT2D, ARID1A, HIST1 members, and TNFRSF14) and PMBL (JAK-STAT pathway genes, B2M, and CD58).

Transcriptional profiles define drug refractory disease in myeloma.

Identifying biomarkers associated with disease progression and drug resistance are important for personalized care. We investigated the expression of 121 curated genes, related to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) responsiveness. We analyzed 28 human multiple myeloma (MM) cell lines with known drug sensitivities and 130 primary MM patient samples collected at different disease stages, including newly diagnosed (ND), on therapy (OT), and relapsed and refractory (RR, collected within 12 months before the patients' death) timepoints.

Longitudinal expression profiling identifies a poor risk subset of patients with ABC-type diffuse large B-cell lymphoma.

Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL.

Causes of death in low-grade B-cell lymphomas in the rituximab era: a prospective cohort study.

Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2015.

Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice.

Purpose: Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression-based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis.

Bendamustine or high-dose cytarabine-based induction with rituximab in transplant-eligible mantle cell lymphoma.

The objective of this study was to explore differences in outcomes between first-line rituximab plus bendamustine (R-B) and R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, dexamethasone, cytarabine, cisplatin) in transplant-eligible patients with mantle cell lymphoma (MCL). A population-based cohort of 97 patients aged 18 to 65 years with stage II-IV MCL, consecutively treated with R-B was retrospectively identified at BC Cancer. Baseline characteristics, response rates, and outcomes were compared with the cohort of 232 patients with MCL randomized to the R-CHOP/R-DHAP arm of the MCL Younger trial.