The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome
Abstract
:1. Introduction
2. Host Genetic Variants Associated to Familial MPNs
3. Host Genetic Variants Associated to Increased MPN Risk in General Population
3.1. The JAK2 46/1 Haplotype
3.2. Telomere Reverse Transcriptase Gene (TERT) Polymorphisms
3.3. Polymorphisms in3q.26 (MECOM and HBS1L-MYB)
3.4. GFI1B and CHEK2 Polymorphisms
4. Host Genetic Variants Modulating Disease Phenotype and/or Outcome
4.1. The rs6198 SNP of the Glucocorticoid Gene
4.2. The rs1024611 SNP of CCL2
4.3. The rs2431697 of MIR146A
5. Host Genetic Variants Affecting Therapy Response
6. Host Genetic Determinants of Clonal Hematopoiesis of Indeterminate Potential (CHIP)
7. Conclusions and Perspectives
- (1)
- Hematopoiesis defines the tightly regulated process of formation of blood and immune cells. To generate these cells, HSCs give rise—throughout individuals’ life span—to an array of committed progenitors, which proliferate extensively and then differentiate into mature cells. Recent advances in genomics, such as accurate deep sequencing and novel methods of cell tracking, revolutionized the concept of hematopoiesis from a process made of discrete, punctuated phenotypic changes to a “continuum model”, typified by a continuous process of differentiation with blurred demarcation between different stages [82,83]. Genetic studies revealed, also, how mechanisms underlying hematopoiesis are modulated by genetic variations present throughout the population. The importance of these host genetic variations is highlighted by the fact that clinically measured hematopoietic traits typically show extensive interindividual variability and are highly heritable, which means that a relevant part of the observed phenotype variations can be attributed to genetic factors [82,84].
- (2)
- During genome duplication, cells may experience different exogenous and endogenous replication stresses, hampering the progression of DNA replication. Replication stress is a phenomenon exacerbated in cancer cells because of the loss of DNA repair genes or the activation of oncogenic pathways [85]. To counteract replication stress, cells are equipped with DNA damage response, an extensive network of signaling pathways accounting for recognition of DNA damage, DNA remodeling and repair, DNA damage bypass during replication, cell cycle control, and cell fate decisions in response to DNA alterations [86]. More than 450 genes are involved in this network. In addition to MPNs, a variety of polymorphisms in DDR genes have been associated with increased risk of developing acute myeloid leukemia [87] and breast cancer [88].
- (3)
- Inflammation refers to a host defense mechanism orchestrated by the immune system in response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation [89]. Cytokines are key mediators of the inflammatory response, by promoting the recruitment and activation of immune cells. After the human leucocyte antigen (HLA), chemokine genes are probably one of the most polymorphic sets of genes in the immune system, with remarkable effects on the immune response. A number of functionally relevant cytokine SNPs have been found repeatedly associated with disease of different etiologies but sharing a common pathogenetic aspect such as chronic inflammation [67].
Author Contributions
Funding
Conflicts of Interest
References
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SNPs | Gene Function (Relative to Hematopoiesis) | Associated Driver Mutations | Associated MPN Phenotype | Ref. |
---|---|---|---|---|
JAK246/1 haplotype | Hematopoiesis, cytokine receptor signaling | All (>JAK2V617F) | All (>PV and PMF) | [9,10,11,12,13] |
TERT | Telomere length | All | All | |
rs2736100 | [10,12] | |||
rs7705526 | [11,13] | |||
rs2853677 | [11,13] | |||
MECOM | HSC maintenance, differentiation | JAK2V617F and CALR type 1/type 1-like | PV MF and ET (only in presence of CALR) | |
rs2201862 | [12] | |||
rs3851397 | [11] | |||
rs9847631 | [13] | |||
HBS1L-MYB rs9376092 | Peripheral blood cell counts, fetal hemoglobin levels | none | ET (only in presence of JAK2V617F) | [11,12] |
GFI1B | HSC quiescence, erythroid and megakaryocytic differentiation | n/a | n/a | |
rs621940 | [11] | |||
rs1633768 | [13] | |||
rs524137 | [13] | |||
CHEK2 | DNA damage response | n/a | n/a | |
rs555607708 | [11] | |||
rs17879961 | [13] | |||
SH2B3 rs7310615 | Negative regulation of normal hematopoiesis | n/a | n/a | [11,13] |
ATM rs1800057 | DNA damage response | n/a | n/a | [11,13] |
TET2 | HSC self-renewal, commitment, terminal differentiation of monocytes | n/a | n/a | |
rs1548483 | [11] | |||
rs62329718 | [13] | |||
PINT rs58270997 | DNA damage response, hematopoietic stem cell maintenance, and differentiation (via PRC2) | n/a | n/a | [11,13] |
THRB-RARB rs4858647 | unknown | none | PMF | [12] |
GATA2 rs9864772 | HSC activity and self-renewal, myeloid and myelo-erythroid differentiation, erythroid precursors maintenance | n/a | n/a | [13] |
SCHIP1 rs77249081 | unknown | n/a | n/a | [13] |
KPNA4 rs74676712 | unknown | n/a | n/a | [13] |
NUDT3 rs116466979 | unknown | n/a | n/a | [13] |
MKLN1 rs61471615 | unknown | n/a | n/a | [13] |
MRPS31 rs8002412 | unknown | n/a | n/a | [13] |
ZNF521 rs9946154 | HSC differentiation and B-lymphoid cell development | n/a | n/a | [13] |
RUNX1 rs55857134 | Differentiation of megakaryocytes and lymphocytes | n/a | n/a | [13] |
SNPs | Gene Function (Relative to Hematopoiesis) | Detection Methods | Allele Variant | MPN Cohort | Disease Subtype Associations | Disease Phenotype Associations | Ref. |
---|---|---|---|---|---|---|---|
JAK2 46/1 haplotype rs12343867 (T/C) | Hematopoiesis, cytokine receptor signaling | RT-PCR | T allele (wild type) | 130 PMF | n/e | ↓ OS | [55] |
RT-PCR | T allele (wild type) | 414 PMF | n/e | ↓ OS | [56] | ||
NR3C1 rs6198 (A/G) | Immune response regulation, erythrocytosis | PCR-SSCP + sequencing | G-allele | 57 MPNs 22 CTRLs | PV | n/e | [57] |
HRM analysis + sequencing | G-allele (homozygous) | 499 PMF 2948 CTRLs | PMF | ↑ CD34+ cells, splenomegaly, ↑WBC, ↓ LFS * | [58] | ||
CCL2rs1024611 (A/G) | Chemokine production | RT-PCR | G-allele | 177 MPNs 149 CTRLs | sMF | ↓ Hb, ↑ IPSS, ↑ blasts, ↑ fibrosis | [59] |
RT-PCR | G-allele (homozygous) | 773 PMF 323 CTRLs | PMF in males | ↓ OS | [60] | ||
MIR146A rs2431697 (C/T) | NF-κB signaling modulation | RT-PCR | T-allele (homozygous) | 967 MPNs 600 CTRLs | sMF | ↓ MF-free survival in PV and ET | [61] |
SNPs | Gene Function (Relative to Hematopoiesis) | Detection Methods | Allele Variant | MPN Cohort | Type of Therapy | Response Assessment | Association(s) | Ref. |
---|---|---|---|---|---|---|---|---|
INFL4 rs12979860 (T/C) | Cytokine production | RT-PCR | C/C | 100 MPNs | Inf α-2b, peg α-2b peg α-2a | HR | Higher HR rate in PVs | [76] |
RT-PCR | C/C | 122 PVs | ropeg α-2b | HR, MR | Higher MR rate | [77] | ||
INFL4 rs368234815 (G/TT) | RT-PCR | TT/TT | 122 PVs | ropeg α-2b | HR, MR | Higher MR rate | [77] | |
INFL4 rs8099917 (T/G) | RT-PCR | T/T |
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Masselli, E.; Pozzi, G.; Carubbi, C.; Vitale, M. The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome. Cells 2021, 10, 2597. https://doi.org/10.3390/cells10102597
Masselli E, Pozzi G, Carubbi C, Vitale M. The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome. Cells. 2021; 10(10):2597. https://doi.org/10.3390/cells10102597
Chicago/Turabian StyleMasselli, Elena, Giulia Pozzi, Cecilia Carubbi, and Marco Vitale. 2021. "The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome" Cells 10, no. 10: 2597. https://doi.org/10.3390/cells10102597