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Genetics of Leukemia and Myelodysplastic Syndromes

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 May 2021) | Viewed by 9187

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Special Issue Editor

Dr. Ota Fuchs

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Guest Editor

Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague 2, Czech Republic
Interests: acute myeloid leukemia; myelodysplastic syndrome; gene expression; prognostic factors; transcription factors; sequencing; del(5q) MDS; immunomodulatory drugs; cereblon; target protein degradation

Special Issue Information

Dear Colleagues,

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by morphological dysplastic changes in one or more of the major hematopoietic cell lines. MDS can present with varying degrees of single or multiple cytopenias including neutropenia, anemia and thrombocytopenia. The risks of MDS include infection, anemia, bleeding and transformation to acute myeloid leukemia (AML) in approximately 30% of cases. The availability of gene-expression analysis and next-generation sequencing (NGS) has led to improvements in clarifying the pathogenesis of MDS and AML, diagnosing these disorders, predicting patient outcomes, therapy selection, and identifying gene mutations as potential therapeutic targets. Recurrent genetic abnormalities in up to 90% of patients with MDS have been identified by NGS. Among major mutational targets in MDS are the molecules involved in DNA methylation, chromatin modification, RNA splicing, transcription, signal transduction, cohesin regulation, and DNA repair. Overlaps of driver mutations in MDS, AML and age-related clonal hematopoiesis in healthy individuals show a common clonal origin. Interactions between mutations play an important role in disease progression. The World Health Organization (WHO) classification included karyotype in the case of del(5q) MDS and SF3B1 somatic mutations as a supplementary criterion for defining MDS with ring sideroblasts. Although most cases of myeloid neoplasms are sporadic, some cases are associated with germline mutations. The purpose of this Special issue is to overview the recent advances in genetics of MDS and AML by reviews or research articles.

Dr. Ota Fuchs
Guest Editor

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Keywords

acute myeloid leukemia
myelodysplastic syndrome
gene expression
next-generation sequencing
mutation
del(5q) MDS
splicing
molecular targeted therapy

Published Papers (3 papers)

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Research

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17 pages, 2531 KiB

Open AccessArticle

Transcriptional Regulation of RUNX1: An Informatics Analysis

by Amarni L. Thomas, Judith Marsman, Jisha Antony, William Schierding, Justin M. O’Sullivan and Julia A. Horsfield

Genes 2021, 12(8), 1175; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081175 - 29 Jul 2021

Cited by 4 | Viewed by 2504

Abstract

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis. Full article

(This article belongs to the Special Issue Genetics of Leukemia and Myelodysplastic Syndromes)

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12 pages, 4560 KiB

Open AccessArticle

Low JAK2 V617F Allele Burden in Ph-Negative Chronic Myeloproliferative Neoplasms Is Associated with Additional CALR or MPL Gene Mutations

by Tatiana V. Makarik, Adhamjon O. Abdullaev, Elena E. Nikulina, Svetlana A. Treglazova, Elena E. Stepanova, Irina N. Subortseva, Alla M. Kovrigina, Anait L. Melikyan, Sergei M. Kulikov and Andrey B. Sudarikov

Genes 2021, 12(4), 559; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040559 - 12 Apr 2021

Cited by 3 | Viewed by 2556

Abstract

JAK2 (Janus kinase 2) V617F, CALR (Calreticulin) exon 9, and MPL (receptor for thrombopoietin) exon 10 mutations are associated with the vast majority of Ph-negative chronic myeloproliferative neoplasms (MPNs). These mutations affect sequential stages of proliferative signal transduction and therefore, after the emergence of one type of mutation, other types should not have any selective advantages for clonal expansion. However, simultaneous findings of these mutations have been reported by different investigators in up to 10% of MPN cases. Our study includes DNA samples from 1958 patients with clinical evidence of MPN, admitted to the National Research Center for Hematology for genetic analysis between 2016 and 2019. In 315 of 1402 cases (22.6%), CALR mutations were detected. In 23 of these 315 cases (7.3%), the JAK2 V617F mutation was found in addition to the CALR mutation. In 16 from 24 (69.6%) cases, with combined CALR and JAK2 mutations, V617F allele burden was lower than 1%. A combination of JAK2 V617F with MPL W515L/K was also observed in 1 out of 1348 cases, only. JAK2 allele burden in this case was also lower than 1%. Additional mutations may coexist over the low background of JAK2 V617F allele. Therefore, in cases of detecting MPNs with a low allelic load JAK2 V617F, it may be advisable to search for other molecular markers, primarily mutations in exon 9 of CALR. The load of the combined mutations measured at different time points may indicate that, at least in some cases, these mutations could be represented by different clones of malignant cells. Full article

(This article belongs to the Special Issue Genetics of Leukemia and Myelodysplastic Syndromes)

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Review

Jump to: Research

22 pages, 1585 KiB

Open AccessReview

Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia

by Mot Yee Yik, Adam Azlan, Yaashini Rajasegaran, Aliaa Rosli, Narazah Mohd Yusoff and Emmanuel Jairaj Moses

Genes 2021, 12(8), 1188; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081188 - 30 Jul 2021

Cited by 7 | Viewed by 3706

Abstract

The proliferative capacity and continuous survival of cells are highly dependent on telomerase expression and the maintenance of telomere length. For this reason, elevated expression of telomerase has been identified in virtually all cancers, including leukemias; however, it should be noted that expression of telomerase is sometimes observed later in malignant development. This time point of activation is highly dependent on the type of leukemia and its causative factors. Many recent studies in this field have contributed to the elucidation of the mechanisms by which the various forms of leukemias increase telomerase activity. These include the dysregulation of telomerase reverse transcriptase (TERT) at various levels which include transcriptional, post-transcriptional, and post-translational stages. The pathways and biological molecules involved in these processes are also being deciphered with the advent of enabling technologies such as next-generation sequencing (NGS), ribonucleic acid sequencing (RNA-Seq), liquid chromatography-mass spectrometry (LCMS/MS), and many others. It has also been established that TERT possess diagnostic value as most adult cells do not express high levels of telomerase. Indeed, studies have shown that prognosis is not favorable in patients who have leukemias expressing high levels of telomerase. Recent research has indicated that targeting of this gene is able to control the survival of malignant cells and therefore offers a potential treatment for TERT-dependent leukemias. Here we review the mechanisms of hTERT regulation and deliberate their association in malignant states of leukemic cells. Further, we also cover the clinical implications of this gene including its use in diagnostic, prognostic, and therapeutic discoveries. Full article

(This article belongs to the Special Issue Genetics of Leukemia and Myelodysplastic Syndromes)

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