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Immune Dysregulation and Recurring Mutations in Myelodysplastic Syndromes Pathogenesis

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Cell Biology and Translational Medicine, Volume 12

Part of the book series: Advances in Experimental Medicine and Biology ((CBTMED,volume 1326))

Abstract

Myelodysplastic syndromes (MDS) are clonal stem cell malignancies characterized by ineffective hematopoiesis leading to peripheral cytopenias and variable risk of progression to acute myeloid leukemia. Inflammation is associated with MDS pathogenesis. Several cytokines, reactive species of oxygen/nitrogen and growth factors are directly or indirectly involved in dysfunction of the MDS bone marrow (BM) microenvironment. Mutations in genes mainly regulating RNA splicing, DNA methylation and chromatin accessibility, transcription factors, signal transduction and the response to DNA damage contribute to ineffective hematopoiesis, genomic instability and MDS development. The inflammation-associated DNA damage in hematopoietic stem cells may also contribute to MDS development and progression with aggressive clinical characteristics. Many studies have aimed at clarifying mechanisms involved in the activity of immature myeloid cells as powerful modulators of the immune response and their correlation with aging, autoimmunity, and development of cancer. In this review, we explore recent advances and accumulating evidence uniting immune dysregulation, inflammaging and recurring mutations in the pathogenesis of MDS.

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Abbreviations

AML:

acute myeloid leukemia

ARG1:

arginase 1

ASXL1:

Additional Sex Combs Like 1, Transcriptional Regulator

BM:

bone marrow

CBL:

Casitas B-Lineage Lymphoma Proto-Oncogene

CCUS:

clonal cytopenia of undetermined significance

CD:

cluster of differentiation

CHIP:

clonal hematopoiesis of indeterminate potential

CSF:

colony-stimulating factor

DAMP:

danger-associated molecular pattern

del:

deletion

DNA:

deoxyribonucleic acid

DNMT3A:

DNA methyltransferase 3A

eMDSC:

early MDSC

ETV6:

ETS Variant Transcription Factor 6

EZH2:

Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit

G:

granulocytic

GATA2:

GATA Binding Protein 2

GM:

granulocyte-monocyte

HLA:

human leukocyte antigen

HSPC:

hematopoietic stem/progenitor cell

IDH1/2:

isocitrate dehydrogenases 1 and 2

IFN-γ:

interferon gamma

IL:

interleukin

IMC:

immature myeloid cell

iNOS:

inducible nitric oxide synthase

IPSS:

International prognostic scoring system

JAK2:

Janus Kinase 2

L-Arg:

L-arginine

M:

monocytic

MDS:

myelodysplastic syndromes

MDSC:

myeloid-derived suppressor cell

miR:

micro RNA

NF-κB:

nuclear factor kappa-light-chain-enhancer of activated B cells

NK:

natural killer

NKT:

natural killer/T

NO:

nitric oxide

NRAS:

Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog

PAMP:

pathogen-associated molecular pattern

PGE2:

prostaglandin E2

PMN:

polymorphonuclear

PPM1D:

Protein Phosphatase, Mg2+/Mn2+ Dependent 1D

RAD21:

RAD21 Cohesin Complex Component

RNA:

ribonucleic acid

ROS:

reactive oxygen species

RUNX1:

RUNX Family Transcription Factor 1

S100A8:

S100 Calcium Binding Protein A8

S100A9:

S100 Calcium Binding Protein A9

SF3B1:

Splicing Factor 3b Subunit 1

SRSF2:

Serine And Arginine Rich Splicing Factor 2

STAG2:

Stromal Antigen 2

TAM:

tumour-associated macrophage

TCR:

T-cell receptor

TET2:

Ten-Eleven Translocation Methylcytosine Dioxygenase 2

TGF-β:

transforming growth factor beta

TIFAB:

TRAF-Interacting Protein with Forkhead-Associated Domain, Family Member B

TIRAP:

Toll-interleukin-1 receptor domain-containing adaptor protein

TLR:

Toll-like receptor

TME:

tumour microenvironment

TNF-α:

tumour necrosis factor alpha

TP53:

Tumour Protein P53

TRAF:

tumor necrosis factor receptor-associated factor

Treg:

regulatory T-cell

U2AF1:

U2 Small Nuclear RNA Auxiliary Factor 1

VEGF:

vascular endothelial growth factor

WT1:

Wilms tumour 1

ZRSR2:

Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2

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Author notes

  1. Authors Silvia M. M. Magalhães and Michael J. Rauh have equally contributed to this chapter.

Authors and Affiliations

  1. Cancer Cytogenomic Laboratory, Federal University of Ceará, Fortaleza, Brazil

    Anacélia Matos & Silvia M. M. Magalhães

  2. Post-graduate Program in Medical Science, Federal University of Ceará, Fortaleza, Brazil

    Anacélia Matos & Silvia M. M. Magalhães

  3. Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Brazil

    Silvia M. M. Magalhães

  4. Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, Canada

    Michael J. Rauh

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  1. Anacélia Matos
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  2. Silvia M. M. Magalhães
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Correspondence to Michael J. Rauh .

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  1. (emeritus), Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Kursad Turksen

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Matos, A., Magalhães, S.M.M., Rauh, M.J. (2020). Immune Dysregulation and Recurring Mutations in Myelodysplastic Syndromes Pathogenesis. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 12. Advances in Experimental Medicine and Biology(), vol 1326. Springer, Cham. https://doi.org/10.1007/5584_2020_608

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