dna hr block Archives - Gen9 Genetics
The advent of massive DNA sequencing technologies has for the first time allowed an extensive look at the heterogeneous spectrum of genes and mutations that underpin myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this review, we wish to explore the most recent advances and the rationale for the potential therapeutic interest of three main actors in myelo-leukemic transformation: transcription factors that govern myeloid differentiation; RNA splicing factors, which ensure adequate mRNA maturation and whose mutations increase the formation of R loops; and desubiquitinating enzymes, which contribute to genome stability in hematopoietic stem cells (HSC).
Abstract
Myeloid neoplasms comprise a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced balance between the self-renewal of hematopoietic stem cells (HSC) and the adequate production of differentiated cells. The origin of the driver mutations that lead to preleukemia can be traced back to the progenitor cells / HSC. Many typical properties of normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and progression. In fact, in turn, different subclones could develop from the original malignant clone through the accumulation of additional mutations, increasing its competitive fitness. Ultimately, this process leads to a complex cancer architecture in which a mosaic of cell clones coexists, each with a unique set of mutations. The repertoire of genes whose mutations contribute to the progression towards leukemogenesis is extensive. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (modifications of DNA and histones), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many actors, transcription factors, RNA splicing proteins, and desubiquitinating enzymes are emerging as potential targets for therapeutic intervention.
Keywords: myelodysplastic syndromes (MDS); acute myeloid leukemia (AML); transcription factors; RNA splicing; Loops in R; genome integrity; desubiquitinating enzymes (DUB)
1. Introduction
Hematopoietic stem cells (HSC) ensure the continuous production of all types of blood cells throughout life. Through a delicate balance between self-renewal, quiescence and differentiation, HSCs maintain homeostatic conditions and respond dynamically to stress stimuli. The balanced production of the different cell lines varies physiologically during aging, when the hematopoietic potential leans progressively towards the myeloid lineages at the expense of the immune cells [1,2,3]. The accumulation of heritable genetic mutations in individual cells and the kinetics of their selection can lead to myeloid neoplasms, a heterogeneous group of diseases characterized by dysfunctional production of myeloid cells in the bone marrow. This can manifest itself in cytopenia and cellular dysplasia, as in myelodysplastic syndromes (MDS), in the overproduction of mature clonal myeloid elements, as in myeloproliferative neoplasms (MPN), or both, as occurs in MDS / MPN, which share different molecular and clinical features and have both myelodysplastic and proliferative characteristics [4]. Myeloid neoplasms carry a high risk of developing into acute myeloid leukemia (secondary AML or s-AML). AML can also develop as a late complication in patients after leukemogenic therapies (therapy-related AML or t-AML), or with no previous MDS clinical history or known exposure to potentially leukemogenic agents (de novo AML) [5]. Driver mutations leading to a pre-leukemia condition originate in HSCs or hematopoietic progenitor stem cells (HSPC). Preleukemic clones can have variable latency and, in some cases, can persist for years before new mutations trigger their leukemic evolution [4,6].
MDS has an estimated crude incidence of 4 to 5 cases per 100,000 people per year. Although MDS occurs in all ages, the incidence is higher in the elderly, with a median age of 70 years at diagnosis [4]. Careful assessment of the prognostic risk, genetics, and age of the individual patient guides the clinical decision-making process [4]. Although the drugs act