Clonal Hematopoiesis of Indeterminate Potential and its Association with Treatment Outcomes and Adverse Events in Patients with Solid Tumors.

Liquid biopsy is increasingly being used in oncology for tumor molecular characterization. CHIP is a common incidental finding in cfDNA, and its prevalence increases with age. This study builds on growing evidence of common CHIP variants in patients with solid tumors.

Cellular and immunotherapies for myelodysplastic syndromes.

In this review article, we outline the current landscape of immune and cell therapy-based approaches for patients with myelodysplastic syndromes (MDS). Given the well characterized graft-versus-leukemia (GVL) effect observed with allogeneic hematopoietic cell transplantation, and the known immune escape mechanisms observed in MDS cells, significant interest exists in developing immune-based approaches to treat MDS. These attempts have included antibody-based drugs that block immune escape molecules, such as inhibitors of the PD-1/PD-L1 and TIM-3/galectin-9 axes that mediate interactions between MDS cells and T-lymphocytes, as well as antibodies that block the CD47/SIRPα interaction, which mediates macrophage phagocytosis.

Plasma versus Tissue Tumor Mutational Burden as Biomarkers of Durvalumab plus Tremelimumab Response in Patients with Metastatic Colorectal Cancer in the CO.26 Trial.

Purpose: Tissue-derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology-agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset in which this was validated lacked colorectal cancers (CRC), and there is limited evidence for immunotherapy benefits in CRC using this threshold.

Patients And Methods: CO.

Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.

Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia.

Multisite clinical cross-validation and variant interpretation of a next generation sequencing panel for lymphoid cancer prognostication.

Aims: Genomic sequencing of lymphomas is under-represented in routine clinical testing despite having prognostic and predictive value. Clinical implementation is challenging due to a lack of consensus on reportable targets and a paucity of reference samples. We organised a cross-validation study of a lymphoma-tailored next-generation sequencing panel between two College of American Pathologists (CAP)-accredited clinical laboratories to mitigate these challenges.

Chronic Lymphocytic Leukemia IGHV Somatic Hypermutation Detection by Targeted Capture Next-Generation Sequencing.

Background: Somatic hypermutation (SHM) status of the immunoglobulin heavy variable (IGHV) gene plays a crucial role in determining the prognosis and treatment of patients with chronic lymphocytic leukemia (CLL). A common approach for determining SHM status is multiplex polymerase chain reaction and Sanger sequencing of the immunoglobin heavy locus; however, this technique is low throughput, is vulnerable to failure, and does not allow multiplexing with other diagnostic assays.

Methods: Here we designed and validated a DNA targeted capture approach to detect immunoglobulin heavy variable somatic hypermutation (IGHV SHM) status as a submodule of a larger next-generation sequencing (NGS) panel that also includes probes for ATM, BIRC3, CHD2, KLHL6, MYD88, NOTCH1, NOTCH2, POT1, SF3B1, TP53, and XPO1.

Spatially Resolved Tumor Microenvironment Predicts Treatment Outcomes in Relapsed/Refractory Hodgkin Lymphoma.

Purpose: About a third of patients with relapsed or refractory classic Hodgkin lymphoma (r/r CHL) succumb to their disease after high-dose chemotherapy followed by autologous stem-cell transplantation (HDC/ASCT). Here, we aimed to describe spatially resolved tumor microenvironment (TME) ecosystems to establish novel biomarkers associated with treatment failure in r/r CHL.

Patients And Methods: We performed imaging mass cytometry (IMC) on 71 paired primary diagnostic and relapse biopsies using a marker panel specific to CHL biology.

Operationalizing Quality Assurance for Clinical Illumina Somatic Next-Generation Sequencing Pipelines.

Quality assurance (QA) is essential for precision oncology workflows, in particular in the clinical setting. However, because of numerous variations in laboratory and bioinformatics pipelines, QA practices remain non-standardized, are often ad hoc, and are lacking longitudinal tracking. A selected review of existing software was performed for quality control of Illumina next-generation sequencing data, focusing specifically on generalizable tools that can be integrated into any bioinformatics workflow to easily develop a QA workflow with longitudinal tracking.

Protocol for performing consecutive bone marrow transplants in mice to study the role of marrow niche in supporting hematopoiesis.

Hematopoietic stem and progenitor cells depend on bone marrow (BM) stromal cells for survival. Here, we present a protocol for performing three consecutive BM transplants in mice to study the role of BM niche in supporting hematopoiesis. We describe steps for transplanting cells to condition the marrow of the recipient mice and transplanting wild-type cells to examine the effect of the conditioned marrow in supporting hematopoiesis.

Shift of the insoluble content of the proteome in the aging mouse brain.

During aging, the cellular response to unfolded proteins is believed to decline, resulting in diminished proteostasis. In model organisms, such as proteostatic decline with age has been linked to proteome solubility shifts and the onset of protein aggregation. However, this correlation has not been extensively characterized in aging mammals.

"I just wanted more": Hereditary cancer syndromes patients' perspectives on the utility of circulating tumour DNA testing for cancer screening.

Hereditary cancer syndromes (HCS) predispose individuals to a higher risk of developing multiple cancers. However, current screening strategies have limited ability to screen for all cancer risks. Circulating tumour DNA (ctDNA) detects DNA fragments shed by tumour cells in the bloodstream and can potentially detect cancers early.

"iNETgrate": integrating DNA methylation and gene expression data in a single gene network.

Integrating multi-omics data in one model can increase statistical power. However, designing such a model is challenging because different omics are measured at different levels. We developed the iNETgrate package (https://bioconductor.

Meis1 establishes the pre-hemogenic endothelial state prior to Runx1 expression.

Hematopoietic stem and progenitor cells (HSPCs) originate from an endothelial-to-hematopoietic transition (EHT) during embryogenesis. Characterization of early hemogenic endothelial (HE) cells is required to understand what drives hemogenic specification and to accurately define cells capable of undergoing EHT. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), we define the early subpopulation of pre-HE cells based on both surface markers and transcriptomes.

Relapse Timing Is Associated With Distinct Evolutionary Dynamics in Diffuse Large B-Cell Lymphoma.

Purpose: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship.

Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML.

Purpose: Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi.

A noncanonical enzymatic function of PIWIL4 maintains genomic integrity and leukemic growth in AML.

RNA-binding proteins (RBPs) form a large and diverse class of factors, many members of which are overexpressed in hematologic malignancies. RBPs participate in various processes of messenger RNA (mRNA) metabolism and prevent harmful DNA:RNA hybrids or R-loops. Here, we report that PIWIL4, a germ stem cell-associated RBP belonging to the RNase H-like superfamily, is overexpressed in patients with acute myeloid leukemia (AML) and is essential for leukemic stem cell function and AML growth, but dispensable for healthy human hematopoietic stem cells.

Relapse timing is associated with distinct evolutionary dynamics in DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is cured in over 60% of patients, but outcomes are poor for patients with relapsed or refractory disease (rrDLBCL). Here, we performed whole genome/exome sequencing (WGS/WES) on tumors from 73 serially-biopsied patients with rrDLBCL. Based on the observation that outcomes to salvage therapy/autologous stem cell transplantation are related to time-to-relapse, we stratified patients into groups according to relapse timing to explore the relationship to genetic divergence and sensitivity to salvage immunochemotherapy.

Control of focal adhesion kinase activation by RUNX1-regulated miRNAs in high-risk AML.

We recently described a 16-gene expression signature for improved risk stratification of acute myeloid leukemia (AML) patients called the AML Prognostic Score (APS). A subset of APS-high-risk AML patients showed increased levels of focal adhesion kinase (FAK), encoded by the Protein Tyrosine Kinase 2 (PTK2) gene, which was correlated with RUNX1 mutations. RUNX1 mutant cells are more sensitive to PTK2 inhibitors.

Computational pathology in 2030: a Delphi study forecasting the role of AI in pathology within the next decade.

Background: Artificial intelligence (AI) is rapidly fuelling a fundamental transformation in the practice of pathology. However, clinical integration remains challenging, with no AI algorithms to date in routine adoption within typical anatomic pathology (AP) laboratories. This survey gathered current expert perspectives and expectations regarding the role of AI in AP from those with first-hand computational pathology and AI experience.

A low carbohydrate diet high in fish oil and soy protein delays inflammation, hematopoietic stem cell depletion, and mortality in miR-146a knock-out mice.

Since our previous studies found a low carbohydrate (CHO) diet containing soy protein and fish oil (15%Amylose/Soy/FO) significantly reduced lung and breast cancer in mice we asked herein if this low CHO diet could also delay the onset of myeloid malignancies. To test this we employed a miR-146a knock-out (KO) mouse model and found the 15%Amylose/Soy/FO diet increased their median lifespan by 8.5 month, compared to these mice on a Western diet.

Single-cell profiling reveals a memory B cell-like subtype of follicular lymphoma with increased transformation risk.

Follicular lymphoma (FL) is an indolent cancer of mature B-cells but with ongoing risk of transformation to more aggressive histology over time. Recurrent mutations associated with transformation have been identified; however, prognostic features that can be discerned at diagnosis could be clinically useful. We present here comprehensive profiling of both tumor and immune compartments in 155 diagnostic FL biopsies at single-cell resolution by mass cytometry.