As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called "clonal hematopoiesis," is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

Clonal hematopoiesis in human aging and disease

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International Consensus Classification of Myeloid Neoplasms and Acute Leukemia: Integrating Morphological, Clinical, and Genomic Data.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

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Acute Myeloid Leukemia, Version 2.2021 Featured Updates to the NCCN Guidelines

DNA methylation is a major epigenetic process that regulates chromatin structure which causes transcriptional activation or repression of genes in a context-dependent manner. In general, DNA methylation takes place when methyl groups are added to the appropriate bases on the genome by the action of "writer" molecules known as DNA methyltransferases. How these methylation marks are read and interpreted into different functionalities represents one of the main mechanisms through which the genes are switched "ON" or "OFF" and typically involves different types of "reader" proteins that can recognize and bind to the methylated regions. A tightly balanced regulation exists between the "writers" and "readers" in order to mediate normal cellular functions. However, alterations in normal methylation pattern is a typical hallmark of cancer which alters the way methylation marks are written, read and interpreted in different disease states. This unique characteristic of DNA methylation "readers" has identified them as attractive therapeutic targets. In this review, we describe the current state of knowledge on the different classes of DNA methylation "readers" identified thus far along with their normal biological functions, describe how they are dysregulated in cancer, and discuss the various anti-cancer therapies that are currently being developed and evaluated for targeting these proteins.

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DNA Methylation Readers and Cancer: Mechanistic and Therapeutic Applications.

Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. ΔMLH1, ΔMSH6, and ΔMSH2 signatures were similar to each other but distinct from ΔPMS2. Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies.

A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage

MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML

Cytosine methylation is essential for normal mammalian development, yet also provides a major mutagenic stimulus. Methylcytosine (5mC) is prone to spontaneous deamination, which introduces cytosine to thymine transition mutations (C>T) upon replication. Cells endure hundreds of 5mC deamination events each day and an intricate repair network is engaged to restrict this damage. Central to this network are the DNA glycosylases MBD4 and TDG, which recognise T:G mispairing and initiate base excision repair (BER). Here we describe a novel cancer predisposition syndrome resulting from germline biallelic inactivation of MBD4 that leads to the development of acute myeloid leukaemia (AML). These leukaemias have an extremely high burden of C>T mutations, specifically in the context of methylated CG dinucleotides (CG>TG). This dependence on 5mC as a source of mutations may explain the remarkable observation that MBD4-deficient AMLs share a common set of driver mutations, including biallelic mutations in DNMT3A and hotspot mutations in IDH1/IDH2. By assessing serial samples taken over the course of treatment, we highlight a critical interaction with somatic mutations in DNMT3A that accelerates leukaemogenesis and accounts for the conserved path to AML. MBD4-deficiency was also detected, rarely, in sporadic cancers, which display the same mutational signature. Collectively these cancers provide a model of 5mC-dependent hypermutation and reveal factors that shape its mutagenic influence.

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Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC

Individual haematologic malignancies are uncommon when compared to solid tumours. Careful definition of distinct subtypes of leukaemias and lymphomas by marrying clinical characteristics with distinct morphological and genetic features has greatly advanced understanding of pathobiology, leading to novel treatments and improved prognoses of different leukaemias and lymphomas. We examine the success stories of acute promyelocytic leukaemia and chronic myeloid leukaemia, and explore how next generation sequencing will empower translational research and treatment advances for rare haematologic malignancies.

Edward Chew

Papers

MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML

Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC

Rare haematologic malignancies: Bad diseases can have great outcomes when the right treatments are discovered

Complexity of DNA Repair From Alcohol Damage Revealed