Page 48 - 2020_08-Haematologica-web

A. Veninga et al.
continued from the previous page
Gene Gene Protein Overall role in Germline/
Inherited disease Somatic Mutation Mutation Thrombosis Bleeding Predisposition Ref.
name
TET2
TP53
(OMIM)
612839
191170
function hematopoiesis
Epigenetic Tumor regulator suppression
somatic
S
G, S
classification (OMIM, PMID) Undefined
Bone marrow
failure syndrome 5 (618165);
Li-Fraumeni syndrome (151623); Adrenocortical carcinoma
pediatric (202300); Basal cell carcinoma 7 (614740); Choroid plexus papilloma (260500); Colorectal cancer (114500); Gliomasusceptibility1 (137800)
Neutropenia severe congenital
X-linked (300299); Thrombocytopenia X-linked (313900); Wiskott-Aldrich syndrome (301000)
phenotype (OMIM, PMID)
Myelodysplastic syndrome somatic (614286)
effect on protein Loss-of- function
effect on platelet traits Count = (m)
Count ↓ (h) = (m), size ↑,
risk risk
Yes No
n.d. n.d.
to malignancy
MDS
Solid cancers, various leukemias
platelet traits 95
71,72
Transcription regulator
Quiescing of HSC; tumor suppression
Breast
cancer
somatic
(114480); function ↓ Hepatocellular (m) carcinoma
Loss-of- function
somatic (114550); Nasopharyngeal carcinoma somatic (607107); Pancreatic cancer somatic (260350); Colorectal cancer (114500);Glioma susceptibility 1 (137800); Osteosarcoma (259500)
Count ↓, unclear
WAS
300392
Signaling Morphogenic regulator development
of HSC
G, S
Juvenile
myelomonocytic function size ↓, lymphoblastic leukemia function leukemia,
77,79
75
(29316027); Somatic mosaicism in Wiskott-Aldrich syndrome (19129986)
Gain-of- function
(h, m) Count ↓/=, size =
n.d. n.d.
MDS, MPD
AML, MDS, JMML
Loss-of-
No Yes
lymphoma,
ALL: acute lymphoblastic leukemia; AMKL: acute megakaryoblastic leukemia; AML: acute myeloid leukemia; CML: chronic myeloid leukemia; CMML: chronic myelomonocytic leukemia; ET: essen- tial thrombocythemia; HSC: hematopoietic stem cell; JMML: juvenile myelomonocytic leukemia; MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasms; OMIM: Online Mendelian Inheritance in Man; PMID: PubMed reference number; PV: polycythemia vera. (h) is mutation effect on platlet trait found in human, (m) is in mice
BRAF
The serine-threonine protein kinase BRAF is an essential partner in the mitogenic RAS/RAF/MEK/ERK signaling pathway. The BRAF proto-oncogene is expressed in all tis- sues, where it controls cell proliferation, apoptosis, and differentiation. In addition, BRAF is necessary for embry- onic development, as Braf-deficient embryos die because of disturbed blood vessel formation.20
Evidence on the role of BRAF in normal megakary- opoiesis comes from work mainly with immortalized human megakaryoblastic cell lines. Upon stimulation with thrombopoietin, differentiation and proliferation of the cells appeared to rely on BRAF-mediated signaling to ERK.21 Downregulation of BRAF thus lowered the number of megakaryocytic lineage cells, a phenomenon that was confirmed in vivo in chimeric mice.20
In the Noonan, LEOPARD and cardiofaciocutaneous syndromes, patients carry germline mutations in BRAF in regions distinct from those of somatic cancerous muta- tions. However, only limited changes in BRAF signaling are reported.22 On the other hand, somatic gain-of-func- tion mutations in the BRAF gene accumulate in patients with AML, malignant lymphomas or solid cancers.23 Next to more common point mutations, rare chromosomal translocations are described for this gene.24
A frequently observed gain-of-function mutation
(V600E) is the driver mutation present in different cancers, including melanomas, solid cancers and hairy cell leukemia (HCL). Patients who suffer from HCL have low blood cell counts, likely due to BM aberrations and splenomegaly.25 Whether megakaryopoiesis is altered due to a constitutively increased MEK/ERK signaling via BRAF still needs to be confirmed.
DNMT3A
Clonal mutations of three genes (DNMT3A, IDH2, TET2) have been reported which, directly or indirectly, affect histone methylation and hence these can be consid- ered as epigenetic regulators.
The gene DNA methyltransferase 3a (DNMT3A) encodes for a DNA methylation enzyme that regulates gene imprinting, chromosome inactivation and tumor suppres- sion. Genetic mutations in the DNMT3A gene occur in the rare Tatton-Brown-Rahman syndrome which, as far as is known, is not accompanied by hematopoietic aberrations.
In several acquired blood cancers, but especially in adults with AML, somatic mutations in DNMT3A have been reported.26 About a quarter of all AML patients with de novo disease carry variant forms of this protein, most commonly with R882H mutation. The loss-of protein- function in those patients resulted in chromosomal islands of hypomethylation.27 The same mutation, albeit less fre-
2024
haematologica | 2020; 105(8)