Page 28 - 2019_01-Haematologica-web

U. Oyarbide et al.
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DC
FA
SDS
CAMT
SCN
DKC1 (91%)
Hypomorphic Dkc1 mutant recapitulate
in the first and second generations (G1 and G2) the clinical features of DC.96
Dkc1Δ15 mice: growth retardation, increased DNA damage response via ATM/p53 pathway. 97
NOLA1 (96%)
N/A
TERT (62%)
Transgenic line over-expressing TERT: short telomeres and increased DNA damage.98
FANCD2 (65%)
FancD2 KO: reduced fertility, growth retardation and increased incidence of tumors.99
BRCA2 (57%)
BRCA2 mutant: embryonic lethality
RAD51 (98%)
Rad51 mutants. Decreased cell proliferation, embryonic lethal.101
SBDS (97%)
Sbds KO: embryonic lethal.102
MPL (80%)
c-Mpl KO. Decrease platelets and megakaryocytes CSF3R (73%)
Csf3R KO. Low number of neutrophils
in peripheral blood.
Expression of truncated Csf3r confers a strong clonal advantage to HSCs.104
SRP54 (99%)
N/A N/A
*Morphant: an organism that has been treated with a morpholino antisense to temporarily knockdown the expression of a gene.
Dkc1 (80%)
N/A dkc1 morphant. Reduced hematopoiesis, increased tp53 expression, and defective
Nola1 (91%)
nola1 mutant. Reduced hematopoiesis, increased tp53 expression, and defective ribosomal biogenesis, no detectable changes in telomerase function.50
Tert (33%)
tert mutant. Tissue atrophy, premature death, sarcopenia, impaired cell proliferation and accumulation of senescence cells.55,57
Fancd2 (53%)
ribosomal biogenesis, no detectable changes in telomerase function.50
N/A
N/A
N/A fancd2 morphant. Shortened body length, microcephaly and abnormally small eyes,
which are due to extensive cellular apoptosis. Upregulation of tp53.63,64
brca2 mutants. Genomic instability.100
Brca2 (41%) Rad51 (93%)
N/A
rad51 mutants. Only infertile males, size N/A reduction, hypocellular kidney marrow.
Double mutants for Rad51 and P53 rescued HSPC defect but showed higher tumor incidence.66
Sbds (87%)
sbds mutant. Size reduction, liver, pancreas and digestive tract atrophy and reduction of neutrophils.78
sbds morphant. Loss of neutrophils, abnormal skeletal architecture and pancreatic hypoplasia. Sbds knockdown phenotype not rescued by loss of tp53.76,77
Mpl (23%)
mpl mutant. Low number of thrombocytes.83 Mpl morphant. Low number of thrombocytes.103 Csf3r (44%)
csf3r mutant. Reduction in neutrophils and myeloid cells in the kidney marrow.87
N/A
Srp54 (95%)
srp54 morphant. Loss of neutrophils and chemotaxis, diminished exocrine pancreas.88
An increase in tp53 expression and its target genes, cdkn1a and mdm2, was observed in rpl11 morphants. Genes involved in apoptosis (bik, bax, puma, and noxa) were also up-regulated.35 Danilova et al. demonstrated that develop- mental and hematopoietic defects, and lower expression of α-E1 globin and hbae1.1 in Rps19-deficient fish were mediated by Tp53 upregulation. Upregulation of tp53 also occurred in zebrafish mutants for rps8, rps11 and rps18.31
Danilova et al. used a zebrafish rpl11 mutant to charac- terize the molecular pathways associated with ribosomal deficiency.36 This mutant showed anemia, decreased
HSCs, and activation of the Tp53 pathway with altered expression in genes involved in cell cycle arrest (cdkn1a and ccng1) and apoptosis (bax and puma). Moreover, abnor- mal regulation of metabolic pathways with a shift from glycolysis to aerobic respiration, upregulation of genes involved in gluconeogenesis and insulin levels, decreased biosynthesis, and increased catabolism were observed. Nucleotide metabolism was affected by upregulation of adenosine deaminase (ada) and xanthine dehydrogenase/oxidase (xdh).33,37 They showed that treat- ment of mutant embryos with an exogenous supply of
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haematologica | 2019; 104(1)