Hematological malignancies comprise a diverse set of
lymphoid and myeloid neoplasms in which normal hematopoiesis has gone awry and together account for ∼10% of all new cancer cases diagnosed in the United States in 2016. Recent intensive genomic sequencing of hemato- poietic malignancies has identified recurrent mutations in genes that encode regulators of chromatin structure and function, highlighting the central role that aberrant epigenetic regulation plays in the pathogenesis of these neoplasms.
A combination of extrinsic and intrinsic factors—including niche-associated factors, signal transduction pathways, transcription factors, and chromatin modifiers—contrib-utes to the dynamic equilibrium between self-renewal and the multipotent differentiation potential of HSCs.
Hematologic malignancies can arise during any stage of
blood cell development and can affect the production and
the function of blood cells with consequences that include an
inability to fight off infections or susceptibility to uncontrolled bleeding.
Hematopoiesis is a highly dynamic developmental process requiring both self-renewal and a well-regulated differentiation process of hematopoietic stem cells (HSCs) to maintain the lifelong regeneration of the mammalian blood cells.
leukemia (accounting for approximately 30% of new diagnoses) can be categorized into acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), and chronic myeloid leukemia (CML). the most common pediatric cancer (ie,
acute lymphoblastic leukemia [ALL]) , nearly 80% of childhood leukemias are ALL.
DNA methylation is dynamically regulated during hematopoietic differentiation, and each DNA methyltransferase plays crucial roles in physiological hematopoiesis. Deletion of Dnmt1 in HSCs demonstrates its requirement for HSC self-renewal and differentiation (Broske et al. 2009; Trowbridge et al. 2009). Hematopoietic-specific disruption of Dnmt3a in mice leads to both increased and decreased DNA methylation at individual loci, and these together contribute to persistent self-renewal and a differentiation block of HSCs (Challen et al. 2012). Dnmt3b knockout alone has a negligible impact on HSC function; however, its deletion along with Dnmt3a further enhances the self-renewal versus differentiation of HSCs (Challen et al. 2014). Studies have revealed that the normal distribution of
methylated cytosines are disrupted in hematological malignancies, and even subtypes of AML have different DNA methylation patterns (Figueroa et al. 2010).
-5mC as diagnostic/prognostic tool
Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia