Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia-like IBMFS ADH5/ALDH2 deficiency

被引:31
作者
Mu, Anfeng [1 ,2 ,3 ]
Hira, Asuka [1 ,2 ]
Niwa, Akira [3 ]
Osawa, Mitsujiro [3 ]
Yoshida, Kenichi [4 ]
Mori, Minako [1 ,2 ,5 ]
Okamoto, Yusuke [1 ,2 ,5 ]
Inoue, Kazuko [6 ]
Kondo, Keita [6 ]
Kanemaki, Masato T. [7 ,8 ]
Matsuda, Tomonari [9 ]
Ito, Etsuro [10 ]
Kojima, Seiji [11 ]
Nakahata, Tatsutoshi [3 ]
Ogawa, Seishi [4 ,12 ,13 ]
Tanaka, Keigo [6 ,14 ]
Matsuo, Keitaro [15 ,16 ]
Saito, Megumu K. [3 ]
Takata, Minoru [1 ,2 ]
机构
[1] Kyoto Univ, Lab DNA Damage Signaling, Dept Late Effects Studies, Radiat Biol Ctr, Kyoto, Japan
[2] Kyoto Univ, Dept Genome Biol, Grad Sch Biostudies, Kyoto, Japan
[3] Kyoto Univ, Dept Clin Applicat, Ctr iPS Cell Res & Applicat, Kyoto, Japan
[4] Kyoto Univ, Dept Pathol & Tumor Biol, Grad Sch Med, Kyoto, Japan
[5] Kyoto Univ, Grad Sch Med, Dept Hematol & Oncol, Kyoto, Japan
[6] Eisai & Co Ltd, Tsukuba, Ibaraki, Japan
[7] Res Org Informat & Syst, Natl Inst Genet, Dept Chromosome Sci, Mishima, Shizuoka, Japan
[8] SOKENDAI Grad Univ Adv Studies, Dept Genet, Mishima, Shizuoka, Japan
[9] Kyoto Univ, Res Ctr Environm Qual Management, Otsu, Shiga, Japan
[10] Hirosaki Univ, Dept Pediat, Grad Sch Med, Hirosaki, Aomori, Japan
[11] Nagoya Univ, Dept Pediat, Grad Sch Med, Nagoya, Aichi, Japan
[12] Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden
[13] Kyoto Univ, Inst Adv Study Human Biol, Kyoto, Japan
[14] Alchemedicine Inc, Tsukuba, Ibaraki, Japan
[15] Aichi Canc Ctr, Div Canc Epidemiol & Prevent, Res Inst, Nagoya, Aichi, Japan
[16] Nagoya Univ, Div Analyt Canc Epidemiol, Grad Sch Med, Nagoya, Aichi, Japan
基金
日本学术振兴会;
关键词
BONE-MARROW FAILURE; FORMALDEHYDE; ALDEHYDES; PATHWAY; DAMAGE; ALDH2;
D O I
10.1182/blood.2020009111
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We have recently discovered Japanese children with a novel Fanconi anemia-like inherited bone marrow failure syndrome (IBMFS). This disorder is likely caused by the loss of a catabolic system directed toward endogenous formaldehyde due to biallelic variants in ADH5 combined with a heterozygous ALDH2*2 dominant-negative allele (rs671), which is associated with alcohol-induced Asian flushing. Phytohemagglutinin-stimulated lymphocytes from these patients displayed highly increased numbers of spontaneous sister chromatid exchanges (SCEs), reflecting homologous recombination repair of formaldehyde damage. Here, we report that, in contrast, patient-derived fibroblasts showed normal levels of SCEs, suggesting that different cell types or conditions generate various amounts of formaldehyde. To obtain insights about endogenous formaldehyde production and how defects in ADH5/ALDH2 affect human hematopoiesis, we constructed disease model cell lines, including induced pluripotent stem cells (iPSCs). We found that ADH5 is the primary defense against formaldehyde, and ALDH2 provides a backup. DNA repair capacity in the ADH5/ALDH2-deficient cell lines can be overwhelmed by exogenous low-dose formaldehyde, as indicated by higher levels of DNA damage than in FANCD2-deficient cells. Although ADH5/ALDH2-deficient cell lines were healthy and showed stable growth, disease model iPSCs displayed drastically defective cell expansion when stimulated into hematopoietic differentiation in vitro, displaying increased levels of DNA damage. The expansion defect was partially reversed by treatment with a new small molecule termed C1, which is an agonist of ALDH2, thus identifying a potential therapeutic strategy for the patients. We propose that hematopoiesis or lymphocyte blastogenesis may entail formaldehyde generation that necessitates elimination by ADH5/ALDH2 enzymes.
引用
收藏
页码:2021 / 2032
页数:12
相关论文
共 28 条
[1]   The interplay of epigenetic marks during stem cell differentiation and development [J].
Atlasi, Yaser ;
Stunnenberg, Hendrik G. .
NATURE REVIEWS GENETICS, 2017, 18 (11) :643-658
[2]   The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy [J].
Barnett, Scott D. ;
Buxton, Iain L. O. .
CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2017, 52 (03) :340-354
[3]   A landscape of germ line mutations in a cohort of inherited bone marrow failure patients [J].
Bluteau, Olivier ;
Sebert, Marie ;
Leblanc, Thierry ;
de latour, Regis Peffault ;
Quentin, Samuel ;
Lainey, Elodie ;
Hernandez, Lucie ;
Dalle, Jean-Hugues ;
de Fontbrune, Flore Sicre ;
Lengline, Etienne ;
Itzykson, Raphael ;
Clappier, Emmanuelle ;
Boissel, Nicolas ;
Vasquez, Nadia ;
Da Costa, Melanie ;
Masliah-Planchon, Julien ;
Cuccuini, Wendy ;
Raimbault, Anna ;
De Jaegere, Louis ;
Ades, Lionel ;
Fenaux, Pierre ;
Maury, Sebastien ;
Schmitt, Claudine ;
Muller, Marc ;
Domenech, Carine ;
Blin, Nicolas ;
Bruno, Benedicte ;
Pellier, Isabelle ;
Hunault, Mathilde ;
Blanche, Stephane ;
Petit, Arnaud ;
Leverger, Guy ;
Michel, Gerard ;
Bertrand, Yves ;
Baruchel, Andre ;
Socie, Gerard ;
Soulier, Jean .
BLOOD, 2018, 131 (07) :717-732
[4]   The Fanconi anaemia pathway: newyplayers and new functions [J].
Ceccaldi, Raphael ;
Sarangi, Prabha ;
D'Andrea, Alan D. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2016, 17 (06) :337-349
[5]   Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart [J].
Chen, Che-Hong ;
Budas, Grant R. ;
Churchill, Eric N. ;
Disatnik, Marie-Helene ;
Hurley, Thomas D. ;
Mochly-Rosen, Daria .
SCIENCE, 2008, 321 (5895) :1493-1495
[6]   Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans [J].
Dingler, Felix A. ;
Wang, Meng ;
Mu, Anfeng ;
Millington, Christopher L. ;
Oberbeck, Nina ;
Watcham, Sam ;
Pontel, Lucas B. ;
Kamimae-Lanning, Ashley N. ;
Langevin, Frederic ;
Nadler, Camille ;
Cordell, Rebecca L. ;
Monks, Paul S. ;
Yu, Rui ;
Wilson, Nicola K. ;
Hira, Asuka ;
Yoshida, Kenichi ;
Mori, Minako ;
Okamoto, Yusuke ;
Okuno, Yusuke ;
Muramatsu, Hideki ;
Shiraishi, Yuichi ;
Kobayashi, Masayuki ;
Moriguchi, Toshinori ;
Osumi, Tomoo ;
Kato, Motohiro ;
Miyano, Satoru ;
Ito, Etsuro ;
Kojima, Seiji ;
Yabe, Hiromasa ;
Yabe, Miharu ;
Matsuo, Keitaro ;
Ogawa, Seishi ;
Goettgens, Berthold ;
Hodskinson, Michael R. G. ;
Takata, Minoru ;
Patel, Ketan J. .
MOLECULAR CELL, 2020, 80 (06) :996-+
[7]   What is the DNA repair defect underlying Fanconi anemia? [J].
Duxin, Julien P. ;
Walter, Johannes C. .
CURRENT OPINION IN CELL BIOLOGY, 2015, 37 :49-60
[8]   Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells [J].
Garaycoechea, Juan I. ;
Crossan, Gerry P. ;
Langevin, Frederic ;
Mulderrig, Lee ;
Louzada, Sandra ;
Yang, Fentang ;
Guilbaud, Guillaume ;
Park, Naomi ;
Roerink, Sophie ;
Nik-Zainal, Serena ;
Stratton, Michael R. ;
Patel, Ketan J. .
NATURE, 2018, 553 (7687) :171-+
[9]   Mechanism of Inhibition for N6022, a First-in-Class Drug Targeting S-Nitrosoglutathione Reductase [J].
Green, Louis S. ;
Chun, Lawrence E. ;
Patton, Aaron K. ;
Sun, Xicheng ;
Rosenthal, Gary J. ;
Richards, Jane P. .
BIOCHEMISTRY, 2012, 51 (10) :2157-2168
[10]  
Gross ER, 2015, ANNU REV PHARMACOL, V55