Regulation of globin-heme balance in Diamond-Blackfan anemia by HSP70/GATA1
Sarah Rio
(1, 2, 3)
,
Marc Gastou
(4, 2, 3)
,
Narjesse Karboul
(1, 2)
,
Raphaёl Derman
(1, 3)
,
Thunwarat Suriyun
(5)
,
Hana Manceau
(1, 3)
,
Thierry Leblanc
(6)
,
Jamel El Benna
(1, 3)
,
Caroline Schmitt
(1, 3, 2, 7)
,
Slim Azouzi
(2, 3, 8)
,
Jérôme Larghero
(9, 3, 10)
,
Zoubida Karim
(1, 2, 3)
,
Alejandra Macias-Garcia
(11)
,
Jane-Jane Chen
(11)
,
Olivier Hermine
(3, 2, 5)
,
Genevieve Courtois
(3, 2, 5)
,
Hervé Puy
(1, 2, 3)
,
Laurent Gouya
(1, 2, 3, 7)
,
Narla Mohandas
(12)
,
Lydie da Costa
(2, 1, 3, 8, 6)
1
CRI (UMR_S_1149 / ERL_8252 / U1149) -
Centre de recherche sur l'Inflammation
2 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge
3 USPC - Université Sorbonne Paris Cité
4 U1170 Inserm - Hématopoïèse normale et pathologique
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 Hôpital Robert Debré
7 Hôpital Louis Mourier - AP-HP [Colombes]
8 BIGR (UMR_S_1134 / U1134) - Biologie Intégrée du Globule Rouge
9 (CIC-BT 301) - CIC - Biotherapie - Saint Louis
10 AP-HP - Hopital Saint-Louis [AP-HP]
11 MIT - Massachusetts Institute of Technology
12 New York Blood Center
2 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge
3 USPC - Université Sorbonne Paris Cité
4 U1170 Inserm - Hématopoïèse normale et pathologique
5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 Hôpital Robert Debré
7 Hôpital Louis Mourier - AP-HP [Colombes]
8 BIGR (UMR_S_1134 / U1134) - Biologie Intégrée du Globule Rouge
9 (CIC-BT 301) - CIC - Biotherapie - Saint Louis
10 AP-HP - Hopital Saint-Louis [AP-HP]
11 MIT - Massachusetts Institute of Technology
12 New York Blood Center
Hana Manceau
- Fonction : Auteur
Jamel El Benna
- Fonction : Auteur
- PersonId : 739956
- IdHAL : jamel-el-benna
- ORCID : 0000-0001-5733-216X
- IdRef : 130373249
Slim Azouzi
- Fonction : Auteur
- PersonId : 780189
- ORCID : 0000-0001-5519-4031
Zoubida Karim
- Fonction : Auteur
- PersonId : 169884
- IdHAL : zoubida-karim
- ORCID : 0000-0002-3724-5592
- IdRef : 174709374
Olivier Hermine
- Fonction : Auteur
- PersonId : 902059
Genevieve Courtois
- Fonction : Auteur
- PersonId : 1057210
Narla Mohandas
- Fonction : Auteur
- PersonId : 762283
- ORCID : 0000-0003-2271-5296
Lydie da Costa
- Fonction : Auteur
- PersonId : 760110
- ORCID : 0000-0001-8806-6941
- IdRef : 089283562
Résumé
Diamond-Blackfan anemia (DBA) is a congenital erythroblastopenia that is characterized by a blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified 2 in vitro erythroid cell growth phenotypes for primary CD34+ cells from DBA patients and following short hairpin RNA knockdown of RPS19, RPL5, and RPL11 expression in normal human CD34+ cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of 2 other ribosomal protein (RP) mutant genes. We further documented that proteasomal degradation of HSP70, the chaperone of GATA1, is a major contributor to the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis, and decreased globin expression, which are all features of the RPL5 or RPL11 DBA phenotype. In the present study, we explored the hypothesis that an imbalance between globin and heme synthesis may be involved in pure red cell aplasia of DBA. We identified disequilibrium between the globin chain and the heme synthesis in erythroid cells of DBA patients. This imbalance led to accumulation of excess free heme and increased reactive oxygen species production that was more pronounced in cells of the RPL5 or RPL11 phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis thereby reducing free heme excess and resulting in decreased apoptosis of DBA erythroid cells. These results demonstrate the involvement of heme in DBA pathophysiology and a major role of HSP70 in the control of balanced heme/globin synthesis.