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The cytogenetic examination of leukemia chromosomes provided the first lines of evidence that cancer was a disease of the genome, supported by the identification of chromosomal translocations that were diagnostic for different leukemia types. These methods gained refinement in the era of whole-genome microarrays and comparative genome hybridization. In the past decade, the application of next-generation sequencing to cancer genome analysis has brought increasing molecular resolution to identifying a myriad of cancer-driving mechanisms, including recurrently altered genes that result from simple nonsynonymous point mutations, insertions or deletions of a few nucleotides (indels), and copy number alterations and other structural variants (translocations and inversions as well as chromosomal arm-level amplifications and deletions) that change the amounts and functions of proteins encoded therein. In addition, similar approaches have uncovered evidence for altered DNA methylation or chromatin packaging caused by differential histone modifications or mutations in chromatin remodelers, DNA methylation regulators, histone modification enzymes, and metabolic enzymes affecting epigenetic cofactors, generally referred to as “epigenomic” modifications. These changes impact cancer-specific gene expression by controlling the density and positioning of nucleosomes and by the use of histone- and DNA-modifying enzymes. Taken together, these different DNA alterations contribute to cancer onset and progression by altering protein function, abundance, or interactions at the level of cellular pathways to arrive at proteomes that promote proliferation, survival, escape from checkpoint controls, and metabolic adaptability. This chapter focuses on examples of technological and analytical approaches used to characterize genomic and epigenomic alterations in hematologic malignancies and their use in research as well as in clinical diagnosis and therapeutic decision making.

Acronyms and Abbreviations

AF, ALL1-fused gene; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; ATAC-seq, uses the hyperactive Tn5 transposase to simultaneously fragment and add sequencing adaptors to accessible DNA; bp, base pair; BAF, BRG/BAF-Associated Factors; BCL, B-cell lymphoma family of regulator proteins that regulate cell death; BET, bromo and extra-terminal; CHD, CHromoDomain Remodeler; ChIP-seq, chromatin immunoprecipitation sequencing; CHIP, clonal hematopoiesis of indeterminate potential; CHOP, clonal hematopoiesis of oncogenic potential; CMML, chronic myelomonocytic leukemia; ddNTP, di-deoxynucleotide triphosphate; DNAme, DNA methylation; DNMT, DNA methyltransferase; dNTP, deoxynucleotide triphosphate; DOT1, a histone H3 methyltransferase; EGR1, early growth response protein 1; Enh, enhancers; EMA, European Medicines Agency; EZH2, enhancer of zeste homolog 2; FDA, U.S. Food and Drug Administration; FFPE, formalin-fixed, paraffin embedded; FLT3-ITD, internal tandem duplications of FLT3 gene; Gb, gigabase, i.e., billion base pairs; GINA, The Genetic Information Nondiscrimination Act; GWAS, genome-wide association study; HAT, histone acetyltransferase; HDAC, histone deacetylase; HIF, hypoxia inducible transcription factor; HMT, histone methyltransferase; HSC, hematopoietic stem cell; H3, histone H3; IDH, isocitrate dehydrogenase; Ifng promoter, interferon gamma promoter; IonChip, the microfluidic sequencing device and pH detection used in the Ion Torrent sequencing system; ISWI, Imitation SWI Remodeler; indel, term for the insertion or the deletion of bases; lncRNA, long noncoding RNA; MDS, myelodysplastic syndromes; miRNA, microRNA; MBD, methyl-domain binding; 5mC, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosine; MLL, Mixed Lineage Leukemia; MTA, metastasis-associated; MRD, minimal residual disease; ...

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