Cll genomics

Our understanding of risk factors for the development of chronic lymphocytic leukemia (CLL) is still incomplete and includes genetic and environmental factors. CLL is one of the most familial of all cancers, yet common high-penetrance risk alleles have not been identified. Genome-wide association studies have identified many common variants with low relative risks, whereas exome-wide rare variant analysis has implicated ATM in CLL causation. Environmental factors have also been challenging to identify given the limited understanding of the relevant time period of exposure relative to diagnosis, and the inability to quantify past exposures...

The molecular landscape of chronic lymphocytic leukemia (CLL) has been extensively characterized, and various potent prognostic biomarkers were discovered. The genetic composition of the B-cell receptor (BCR) immunoglobulin (IG) was shown to be especially powerful for discerning indolent from aggressive disease at diagnosis. Classification based on the IG heavy chain variable gene (IGHV) somatic hypermutation status is routinely applied. Additionally, BCR IGH stereotypy has been implicated to improve risk stratification, through characterization of subsets with consistent clinical profiles...

Chromosomal aberrations are a common feature of cancer and can fuel cancer progression and treatment resistance. In chronic lymphocytic leukemia (CLL), the presence of multiple chromosomal aberrations is commonly referred to as "genomic complexity" or "complex karyotype"- (CKT). In the context of chemo- and chemoimmunotherapy, genomic complexity is associated with poor response to treatment and short survival, while some targeted therapies are able to mitigate its adverse prognostic impact. This article reviews currently available data and literature on the role of genomic complexity in CLL...

BACKGROUND: High expression of the glycosyltransferase UGT2B17 represents an independent adverse prognostic marker in chronic lymphocytic leukemia (CLL). It also constitutes a predictive marker for therapeutic response and a drug resistance mechanism. The key determinants driving expression of the UGT2B17 gene in normal and leukemic B-cells remain undefined. The UGT2B17 transcriptome is complex and is comprised of at least 10 alternative transcripts, identified by previous RNA-sequencing of liver and intestine...

POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape...

Allele-specific methylation (ASM) is an epigenetic modification whereby one parental allele becomes methylated and the other unmethylated at a specific locus. ASM is most often driven by the presence of nearby heterozygous variants that influence methylation, but also occurs somatically in the context of genomic imprinting. In this study, we investigate ASM using publicly available single-cell reduced representation bisulfite sequencing (scRRBS) data on 608 B cells sampled from six healthy B cell samples and 1,230 cells from 11 chronic lymphocytic leukemia (CLL) samples...

Patients with chronic lymphocytic leukemia (CLL) have differing clinical outcomes. Recent advances integrating multi-omic data have uncovered molecular subtypes in CLL with different prognostic implications and may allow better prediction of therapy response. While finite-duration chemoimmunotherapy (CIT) has enabled deep responses and prolonged duration of responses in the past, the advent of novel targeted therapy for the treatment of CLL has dramatically changed the therapeutic landscape. In this review, we discuss the latest genomic, transcriptomic, and epigenetic alterations regarded as major drivers of resistance to CIT in CLL...

Clonal expansion of B-cells, from the early stages of monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases to Richter's syndrome (RS) provides a comprehensive model of cancer evolution, notable for the marked morphological transformation and distinct clinical phenotypes. High-throughput sequencing of large cohorts of patients and single-cell studies have generated a molecular map of CLL and more recently, of RS, yielding fundamental insights into these diseases and of clonal evolution...

With the advent of outperforming and massive laboratory tools, such as multiparameter flow cytometry and next-generation sequencing, hematopoietic cell clones with putative abnormalities for a variety of blood malignancies have been appreciated in otherwise healthy individuals. These conditions do not fulfill the criteria of their presumed cancer counterparts, and thus have been recognized as their precursor states. This is the case of monoclonal gammopathy of unknown significance (MGUS), the first blood premalignancy state described, preceding multiple myeloma (MM) or Waldenström macroglobulinemia (WM)...

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. Although various patterns of lung involvement with CLL have been reported, data on clinicoradiologic presentation are sparse. METHODS: A computer-assisted search was conducted to identify patients encountered at Mayo Clinic from 1998 to 2022 and had leukemic pulmonary infiltrates (LPI) with CLL demonstrated on lung biopsy. Medical records and chest imaging studies were reviewed to identify clinical and radiologic features...

T(14;19) is an unusual but distinct genomic alteration reported in low-grade B-cell lymphomas. This structural rearrangement places BCL3 in juxtaposition with IGH inducing proliferation and has been found in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), and other low-grade B-cell lymphomas. While there are some case series describing this in the context of other cytogenetic alterations, there are limited clinical cases examined from a molecular perspective...

Chronic lymphocytic leukemia (CLL) is characterized by widespread alterations in the genetic and epigenetic landscapes which seem to underlie the variable clinical manifestations observed in patients. Over the last decade, epigenomic studies have described the whole-genome maps of DNA methylation and chromatin features of CLL and normal B cells, identifying distinct epigenetic mechanisms operating in tumoral cells. DNA methylation analyses have identified that the CLL methylome contains imprints of the cell of origin, as well as of the proliferative history of the tumor cells, with both being strong independent prognostic predictors...

Bruton's tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant B-cells in chronic lymphocytic leukemia (CLL). Small molecule BTK inhibitors were designed to bind BTK's active site and block downstream signaling. These drugs have now been used in the treatment of thousands of patients with CLL, the most common form of leukemia in the western hemisphere. However, adverse effects of early generations of BTK inhibitors and resistance to treatment have led to the development of newer, more selective and non-covalent BTK inhibitors...

Epstein-Barr virus-related malignancies have been linked to variations in the sequences of EBV genes, notably EBNA1. Therefore, the purpose of this study was to examine the DBD/DD domain and USP7 binding domain sequences at the C-terminus of the EBNA1 gene in patients with chronic lymphocytic leukemia (CLL). This study included 40 CLL patients and 21 healthy volunteers. Using commercial kits, total DNA was extracted from buffy coat samples, and each sample was tested for the presence of the EBV genome. The C-terminus of EBNA1 was then amplified from positive samples, using nested PCR...

Large-scale next-generation sequencing (NGS) studies revealed extensive genetic heterogeneity, driving a highly variable clinical course of chronic lymphocytic leukaemia (CLL). The evolution of subclonal populations contributes to diverse therapy responses and disease refractoriness. Besides, the dynamics and impact of subpopulations before therapy initiation are not well understood. We examined changes in genomic defects in serial samples of 100 untreated CLL patients, spanning from indolent to aggressive disease...

Background: Automating data analysis pipelines is a key requirement to ensure reproducibility of results, especially when dealing with large volumes of data. Here we assembled automated pipelines for the analysis of High-throughput Sequencing (HTS) data originating from RNA-Seq, ChIP-Seq and Germline variant calling experiments. We implemented these workflows in Common workflow language (CWL) and evaluated their performance by: i) reproducing the results of two previously published studies on Chronic Lymphocytic Leukemia (CLL), and ii) analyzing whole genome sequencing data from four Genome in a Bottle Consortium (GIAB) samples, comparing the detected variants against their respective golden standard truth sets...

Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with a heterogeneous clinical behavior. In 5-10% of patients the disease transforms into a diffuse large-B cell lymphoma known as Richter transformation (RT), which is associated with dismal prognosis. Here, we aimed to establish patient-derived xenograft (PDX) models to study the molecular features and evolution of CLL and RT. We generated two PDXs by injecting CLL (PDX12) and RT (PDX19) cells into immunocompromised NSG mice. Both PDXs were morphologically and phenotypically similar to RT...

A panel of chronic lymphocytic leukemia (CLL) experts from Tuscany propose a real-life diagnostic and therapeutic approach CLL that considers the role of genomic and somatic prognostic factors in risk stratification and treatment decisions. Safety and efficacy of new agents has been demonstrated now not only in clinical trials but also in many real-world series. The BTK inhibitors, ibrutinib and acalabrutinib, and BH3 mimetic venetoclax are now indicated as first-line therapy and chemoimmunotherapy can be spared to the majority of CLL patients, thus preventing unnecessary hematological and non-hematological toxicity and second primary tumors...

The immune-modulating protein CD52 attenuates lymphocyte function and is associated with autoimmune disorders, for example, multiple sclerosis (MS). CD52 represents a therapeutic target in MS and chronic lymphocytic leukemia (CLL). Its expression has prognostic and predictive value in CLL and is prognostic in breast cancer. Its significance in melanoma is unclear. We analyzed CD52 mRNA expression data from tumor bulk tissues of N = 445 untreated melanoma patients from The Cancer Genome Atlas (TCGA) Research Network and of N = 121 melanoma patients undergoing anti-PD-1 immune checkpoint blockade (ICB) with regard to outcome (overall survival [OS], disease control [DC], and progression-free survival [PFS]), single-cell RNA-Seq data of N = 4645 cells from N = 19 melanoma tissues, and N = 15,457 cells from normal skin provided by N = 5 donors...

PURPOSE: Mutations in BTK, PLCG2, and BCL2 have been reported in patients with progressive disease (PD) on continuous single-agent BTK or BCL2 inhibitor treatment. We tested for these mutations in samples from patients with PD after completion of first-line treatment with fixed-duration ibrutinib plus venetoclax for chronic lymphocytic leukemia (CLL) in the phase II CAPTIVATE study. PATIENTS AND METHODS: A total of 191 patients completed fixed-duration ibrutinib plus venetoclax (three cycles of ibrutinib then 12-13 cycles of ibrutinib plus venetoclax)...