Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition
Abstract
:1. Introduction
2. Transcription Control
2.1. CEBPA
2.2. RUNX1
2.3. GATA2
3. Splicing and Signal Transduction Control
3.1. DDX41
3.2. SMAD9 and SMAD9L
3.3. RAS/MAPK Pathway
4. Bone Marrow Failure Syndromes and Other Inherited Disorders
4.1. Fanconi Anemia (FA)
4.2. Dyskeratosis Congenita (DC)
4.3. Diamond–Blackfan Anemia (DBA)
4.4. Li–Fraumeni Syndrome
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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MN with germline predisposition without a preexisting disorder or organ dysfunction | AML with germline CEBPA mutation |
MN with germline DDX41 mutation | |
MN with germline predisposition and preexisting platelet disorder | MN with germline RUNX1 mutation |
MN with germline ANKRD26 mutation | |
MN with germline ETV6 mutation | |
MN with germline predisposition and other rgan dysfunction | MN with germline GATA2 mutation |
MN associated with bone marrow failure syndromes | |
MN associated with telomere biology disorders | |
Juvenile myelomonocytic leukemia associated with neurofibromatosis, Noonan syndrome, or Noonan-syndrome-like disorders | |
MN associated with Down syndrome |
Gene (chr. Band) | Syndrome Name | Key Clinical and Pathologic Features | Mechanism | References |
---|---|---|---|---|
ANKRD26 (10p12.1) | Thrombocytopenia 2 | Thrombocytopenia/platelet dysfunction No organ dysfunction MDS, AML, rarely CML, CMML | ANKRD26 germline missense mutations result in increased MPL signaling pathway and impaired pro-platelet formation by megakaryocytes; ANKRD26 promoter mutations prevent RUNX1 binding to the promoter, resulting in consecutive activation of MAPK signaling and abnormal platelet function. | WHO 2017 NCCN 2021 [47,48] |
ATG2B (14q32.2) GSKIP (14q32.2) | MNs with germline predisposition due to duplications of ATG2B and GSKIP | ET or PMF progress to AML, CMML, CML, aCML Penetrance > 80% | An approximately 700 kb tandem duplication results in overexpression of ATG2B and GSKIP, enhancing sensitivity to thrombopoietin; cooperates with acquired JAK2, MPL, and CALR mutations during MPN development. | NCCN 2021 [49,50] |
CBL (11q23.3) | CBL syndrome | JMML, clonal macrophage/monocyte proliferation | CBL is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase, which plays a role in tyrosine kinase signaling; the mutational spectrum is mainly missense variants or splice-site variants in the linker region and zinc-coordinating amino acids of the RING finger domain. Heterozygous germline variants are typically accompanied by copy-neutral loss of heterozygosity (CN-LOH) of the 11q23 region with the consecutive homozygous state of the CBL variant; thus, a high allele frequency of the identified CBL variant or CN-LOH at 11q23 is suggestive of CBL syndrome. | [35,51,52] |
CEBPA (19q13.11) | Familial AML with mutated CEBPA | AML (normal karyotype, blasts have aberrant CD7 expression) No organ dysfunction Median age at diagnosis: 25 years ~100% penetrance | The gene encodes granulocyte differentiation factor. Germline mutations are typically N-terminal and frame-shift variants. C-terminal mutations are typically somatic and in-frame insertions, deletions, frameshift, or missense variants; they are typically unstable, and a novel clone during recurrence is not unusual. Acquired mutations in GATA2 and WT1 are common and mutually exclusive. | WHO 2017 NCCN 2021 [6,47,53] |
DDX41 (5q35.3) | Familial AML with mutated DDX41 | MDS, AML, CMML, CML Normal karyotype in 80% of patients No organ dysfunction Median age at diagnosis is 62 years | DEAD/H-box helicase gene encodes an RNA helicase protein with a function in RNA splicing. Many patients have biallelic mutations (frameshift, missense, splicing). Although rare in MNs (1.5%), if detected, DDX41 mutation is germline in 50% of cases. | WHO 2017 NCCN 2021 [23,24,47] |
ETV6 (12p13.2) | MNs with germline ETV6 mutation/Thrombocytopenia 5 | Thrombocytopenia/platelet dysfunction and no organ dysfunction ALL, MDS, AML, CMML, PV, aplastic anemia | The gene encodes a transcription factor. Mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative effect, and impair expression of platelet-associated genes with defective maturation of megakaryocytes. Germline variants are associated with lymphoid and myeloid neoplasms. | WHO 2017 NCCN 2021 [54,55,56] |
GATA2 (3q21.3) | Familial MDS/AML with mutated GATA2 (known as GATA2 deficiency syndromes) | Organ dysfunction (lymphedema, hydrocele, congenital deafness, vulnerability to viral infections) 70–75% penetrance MDS, AML, common in children with MDS and monosomy 7 Dysplasia is frequent, particularly dysmegakaryopoiesis | Gata2 is a zinc-finger transcription factor that is important in the control of hematopoiesis and autoimmunity; germline mutations are loss-of-function variants. Mutations are frequent in MDS and AML cases together with ASXL1 mutations, indicative of a possible collaborative mechanism. | WHO 2017 NCCN 2021 [18,21,57,58,59,60] |
MBD4 (3q21.3) | Familial AML with mutated MBD4 | AML | MBD4, methyl-CpG binding domain 4, encodes a DNA glycosylase that removes base lesions and initiates DNA repair. MBD4-deficiency AML displays a 33-fold higher mutation burden, with mostly C>T in CG dinucleotide; has a propensity for DNMT3A-mutated clonal hematopoiesis. | [61] |
MECOM (3q26.2) | MECOM-associated syndrome (also known as congenital amegakaryocytic thrombocytopenia and radioulnar synostosis) | Amegakaryocytic thrombocytopenia, bone marrow failure, MDS Organ dysfunction (radiosynostosis, clinodactyly, presenile hearing loss, cardiac/renal malformations) | A range of genetic variants have been observed, including gene deletions and point mutations. Mutations are clustered within the 8th zinc-finger motif of the C-terminal zinc-finger domain of EVI1. | [62,63,64] |
RUNX1 (21q22) | Familial platelet disorder with propensity for myeloid malignancies | MDS, AML, thrombocytopenia, platelet dysfunction, CMML No organ dysfunction Median age at diagnosis is 39 years old; lifetime risk of myeloid neoplasm is ~20~65%. | The gene encodes a transcription factor with a major role in megakaryocyte maturation, differentiation, ploidization, and pro-platelet formation. Germline mutations are typically frameshift or missense all over the gene, but predominantly in the RUNT domain and transactivation domain. | WHO 2017 NCCN 2021 [15,16,47,65] |
SAMD9 (7q21.2) SAMD9L (7q21.2) | Congenital SAMD9/SAMD9L mutations MIRAGE syndrome/ Monosomy 7 myelodysplasia and leukemia syndrome 2/Ataxia pancytopenia syndrome | MDS, AML, pancytopenia Organ dysfunction (hematopoietic, immunologic, endocrine, genital, neurologic) Together with GATA2-mutated myeloid neoplasms are the most frequent oncogenic drivers in pediatric MDS (half of pediatric MDS with monosomy 7) Penetrance is not complete | SAMD9 encodes sterile alpha motif domain-containing protein 9, which is involved in endosome fusion and plays a role in signal transduction and proliferation. SAMD9L is a paralog (L stands for -like) and a negative controller of proliferation. Germline mutations cause gain of function of SAMD9 and SAMD9L, which normally results in suppression of myeloid proliferation and inhibits cell cycle progression, leading to pancytopenias, as well as other organ hypoplasias and growth restrictions. | [29,31,60,66,67] |
SRP72 (4q12) | Familial aplastic anemia/MDS with SRP72 mutation | MDS, aplastic anemia, familial leukemia, bone marrow failure | SRP72 is a component of the signal recognition particle, a ribonucleoprotein complex responsible for the translocation of nascent membrane-bound and excreted proteins to the endoplasmic reticulum. | [68] |
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Gao, J.; Chen, Y.; Sukhanova, M. Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition. Life 2022, 12, 46. https://doi.org/10.3390/life12010046
Gao J, Chen Y, Sukhanova M. Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition. Life. 2022; 12(1):46. https://doi.org/10.3390/life12010046
Chicago/Turabian StyleGao, Juehua, Yihua Chen, and Madina Sukhanova. 2022. "Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition" Life 12, no. 1: 46. https://doi.org/10.3390/life12010046
APA StyleGao, J., Chen, Y., & Sukhanova, M. (2022). Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition. Life, 12(1), 46. https://doi.org/10.3390/life12010046