scholarly journals Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

2020 ◽  
Vol 6 (51) ◽  
pp. eabd7197
Author(s):  
Yasuyoshi Oka ◽  
Motoharu Hamada ◽  
Yuka Nakazawa ◽  
Hideki Muramatsu ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Dna Damage ◽  
Clinical Features ◽  
Multisystem Disorder ◽  
Hematopoietic Stem ◽  
Proliferation Capacity ◽  
Short Life Span ◽  
Defective Allele ◽  
Alcohol Flushing ◽  
Aldehyde Dehydrogenase 2 Gene ◽  
Differentiation And Proliferation

Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5−/−Aldh2E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

scholarly journals Genetic control of the frequency of hematopoietic stem cells in mice: mapping of a candidate locus to chromosome 1.

1996 ◽  
Vol 183 (3) ◽  
pp. 1141-1150 ◽  
Author(s):  
C E Müller-Sieburg ◽  
R Riblet
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Inbred Strains ◽  
Cell Number ◽  
Chromosome 1 ◽  
Cell Frequency ◽  
Candidate Locus ◽  
Hematopoietic Stem ◽  
Differentiation And Proliferation

The genetic elements that govern the differentiation and proliferation of hematopoietic stem cells remain to be defined. We describe here marked strain-specific differences in the frequency of long-term culture-initiating cells (LTC-IC) in the bone marrow of different strains of mice. Mice of C57Bl/6 background showed the lowest levels of stem cells in marrow, averaging 2.4 +/- .06 LTC-IC/10(5) cells, BALB/c is intermediate (9.1 +/- 4.2/10(5) cells), and DBA/2 mice contained a 11-fold higher frequency of LTC-IC (28.1 +/- 16.5/10(5) cells) than C57Bl/6 mice. The genetic factors affecting the size of the stem cell pool were analyzed in the C57Bl/6 X DBA/2 recombinant inbred strains; LTC-IC frequencies ranged widely, indicating that stem cell frequencies are controlled by multiple genes. Quantitative trait linkage analysis suggested that two loci that have major quantitative effects are located on chromosome 1 near Adprp and Acrg, respectively. The mapping of the locus near Adprp was confirmed by finding an elevated stem cell frequency in B6.C-H25, a C57Bl/6 congenic strain that carries a portion of chromosome 1 derived from BALB/c mice. We have named this gene Scfr1 (stem cell frequency regulator 1). The allelic forms of this gene may be an important predictor of stem cell number and thus would be useful for evaluating cell sources in clinical stem cell transplantation.

Clinical features and survival of 338 multiple myeloma patients treated with hematopoietic stem cell transplantation or conventional chemotherapy

2015 ◽  
Vol 96 (4) ◽  
pp. 417-424 ◽  
Author(s):  
Raúl Pérez ◽  
Mª Sol Durán ◽  
Jose Mayans ◽  
Alfons Soler ◽  
Inmaculada Castillo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Clinical Features ◽  
Conventional Chemotherapy ◽  
Hematopoietic Stem

scholarly journals ¬¬Attenuated DNA Damage Responses and Increased Apoptosis Characterize Human Hematopoietic Stem Cells Exposed to Irradiation

2018 ◽  
Vol 64 ◽  
pp. S87
Author(s):  
Michael Milyavsky ◽  
Shahar Biechonski ◽  
Leonid Olender ◽  
Adi Zipin-Roitman ◽  
Muhammad Yassin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Dna Damage Responses

scholarly journals Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions

Blood ◽  
2017 ◽  
Vol 130 (13) ◽  
pp. 1523-1534 ◽  
Author(s):  
Ana Martín-Pardillos ◽  
Anastasia Tsaalbi-Shtylik ◽  
Si Chen ◽  
Seka Lazare ◽  
Ronald P. van Os ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dysfunction ◽  
Replication Stress ◽  
Precursor Cells ◽  
Dna Lesions ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Functional Integrity ◽  
Key Points

Key Points Tolerance of oxidative DNA lesions ensures the genomic and functional integrity of hematopoietic stem and precursor cells. Endogenous DNA damage–induced replication stress is associated with mitochondrial dysfunction.

Overexpression of HOXB4 enhances the hematopoietic potential of embryonic stem cells differentiated in vitro

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2740-2749 ◽  
Author(s):  
CD Helgason ◽  
G Sauvageau ◽  
HJ Lawrence ◽  
C Largman ◽  
RK Humphries
Keyword(s):  
Stem Cells ◽  
Es Cells ◽  
Hematopoietic Cells ◽  
Embryonic Stem ◽  
Homeobox Genes ◽  
Embryoid Bodies ◽  
Proliferative Potential ◽  
Hematopoietic Stem ◽  
Differentiation And Proliferation

Little is known about the molecular mechanisms controlling primitive hematopoietic stem cells, especially during embryogenesis. Homeobox genes encode a family of transcription factors that have gained increasing attention as master regulators of developmental processes and recently have been implicated in the differentiation and proliferation of hematopoietic cells. Several Hox homeobox genes are now known to be differentially expressed in various subpopulations of human hematopoietic cells and one such gene, HOXB4, has recently been shown to positively determine the proliferative potential of primitive murine bone marrow cells, including cells with long-term repopulating ability. To determine if this gene might influence hematopoiesis at the earliest stages of development, embryonic stem (ES) cells were genetically modified by retroviral gene transfer to overexpress HOXB4 and the effect on their in vitro differentiation was examined. HOXB4 overexpression significantly increased the number of progenitors of mixed erythroid/myeloid colonies and definitive, but not primitive, erythroid colonies derived from embryoid bodies (EBs) at various stages after induction of differentiation. There appeared to be no significant effect on the generation of granulocytic or monocytic progenitors, nor on the efficiency of EB formation or growth rate. Analysis of mRNA from EBs derived from HOXB4-transduced ES cells on different days of primary differentiation showed a significant increase in adult beta-globin expression, with no detectable effect on GATA-1 or embryonic globin (beta H-1). Thus, HOXB4 enhances the erythropoietic, and possibly more primitive, hematopoietic differentiative potential of ES cells. These results provide new evidence implicating Hox genes in the control of very early stages in the development of the hematopoietic system and highlight the utility of the ES model for gaining insights into the molecular genetic regulation of differentiation and proliferation events.

scholarly journals Precise Gene Editing Preserves Hematopoietic Stem Cell Function following Transient p53-Mediated DNA Damage Response

2019 ◽  
Vol 24 (4) ◽  
pp. 551-565.e8 ◽  
Author(s):  
Giulia Schiroli ◽  
Anastasia Conti ◽  
Samuele Ferrari ◽  
Lucrezia della Volpe ◽  
Aurelien Jacob ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Dna Damage Response ◽  
Gene Editing ◽  
Cell Function ◽  
Hematopoietic Stem ◽  
Damage Response

scholarly journals Microwaves from mobile phone induce reactive oxygen species but not DNA damage, preleukemic fusion genes and apoptosis in hematopoietic stem/progenitor cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Matus Durdik ◽  
Pavol Kosik ◽  
Eva Markova ◽  
Alexandra Somsedikova ◽  
Beata Gajdosechova ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Flow Cytometry ◽  
Dna Damage ◽  
Mobile Phone ◽  
Progenitor Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Fusion Genes ◽  
Microscopy Imaging ◽  
Hematopoietic Stem

Abstract Exposure to electromagnetic fields (EMF) has been associated with the increased risk of childhood leukemia, which arises from mutations induced within hematopoietic stem cells often through preleukemic fusion genes (PFG). In this study we investigated whether exposure to microwaves (MW) emitted by mobile phones could induce various biochemical markers of cellular damage including reactive oxygen species (ROS), DNA single and double strand breaks, PFG, and apoptosis in umbilical cord blood (UCB) cells including CD34+ hematopoietic stem/progenitor cells. UCB cells were exposed to MW pulsed signals from GSM900/UMTS test-mobile phone and ROS, apoptosis, DNA damage, and PFG were analyzed using flow cytometry, automated fluorescent microscopy, imaging flow cytometry, comet assay, and RT-qPCR. In general, no persisting difference in DNA damage, PFG and apoptosis between exposed and sham-exposed samples was detected. However, we found increased ROS level after 1 h of UMTS exposure that was not evident 3 h post-exposure. We also found that the level of ROS rise with the higher degree of cellular differentiation. Our data show that UCB cells exposed to pulsed MW developed transient increase in ROS that did not result in sustained DNA damage and apoptosis.

scholarly journals The Defective Allele of Aldehyde Dehydrogenase 2 Gene is Associated with Favorable Postoperative Prognosis in Hepatocellular Carcinoma

2019 ◽  
Vol 10 (23) ◽  
pp. 5735-5743 ◽  
Author(s):  
Po-Han Huang ◽  
Ching-Chih Hu ◽  
Cheng-Hung Chien ◽  
Li-Wei Chen ◽  
Rong-Nan Chien ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Aldehyde Dehydrogenase ◽  
Aldehyde Dehydrogenase 2 ◽  
Postoperative Prognosis ◽  
Defective Allele ◽  
Aldehyde Dehydrogenase 2 Gene
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