depletion of RPS19, RPL5 or RPL11 by specific shRNA, leading to p21, Bax and Noxa increased
expression, increased apoptosis (after RPL5 and RPL11 depletion) and cell cycle arrest in
G0/G1 phasis (19, 20). Thus, p53 at least in part has been shown to be responsible for DBA
erythroid defect meanwhile the level of p53 is different between mutated RP. But it still does
not explain the erythroid tropism of DBA since p53 is stabilized also in the other IBMFs. In
order to pursue this investigation, we and other groups found that GATA1 and HSP70 are the
major factors involved in DBA pathophysiology and in particular the DBA erythroid tropism.
Indeed, Sankaran’s group (21) identified that GATA1 mRNA translation is specifically affected
in DBA due the 5’UTR characteristics of GATA1 gene. In addition, we found that HS70, the
chaperone of GATA1 during terminal erythroid differentiation was degraded by proteasomal
degradation after ubiquitinylation, unable to protect GATA1 from the cleavage by the caspase
3, decreasing GATA1 expression, activating largely p53, leading to increased apoptosis and
delayed erythroid differentiation in patients mutated in RPL5 or RPL11 or any patients not
mutated in RPS19, who exhibited normal HSP70 expression, normal erythroid differentiation,
and no or little apoptosis (22). In addition, the defect in GATA1 is responsible for the defect in
GATA1 targets, such as globin chains and ALAS2. In the attempt of the cell to decrease the
amount of free heme content and restore the level of globin translation to the level of heme
synthesis to maintain the equilibrium globins/heme to produce hemoglobulin, erythroid cells
decrease heme synthesis by decreasing mitochondrial ALAS2 and ferrochelatase enzyme
production and increase i) the expression of the heme exporter FLVCR1a, and ii) the globin
translation after inhibition of the phosphorylation of EIF2a (inactive HRI), and after Bach1
proteasomal degradation. We showed that increase heme content in erythroid cells in
mutated RPL5 and RPL11 affected DBA patients, lead to increase reactive oxygen species
(ROS) production, which was responsible, with increased apoptosis for cell death,
participating as well to the DBA erythroid intrinsic defect (23). In resume, in 2021, the DBA
pathophysiology and in particular its tropism for an erythroid defect is at least in part much
better understood. It involved an activation of p53, a decreased ribosome amount, a
decreased in GATA1 translation and not exclusively, a defect of GATA1 due to the HSP70
decreased expression, decreased globin chain synthesis, unbalanced globin/heme equilibrium
in favor of the free heme content, which increased cell toxicity producing large amount of
ROS, and affecting the ribosome biogenesis (6). The degree of each factor involvement may
be responsible for the heterogenous phenotype of the DBA patients. No doubt that research
in the near future will decipher the dark areas remaining in DBA pathophysiology, will identify
new candidate genes and new therapeutic targets for a disease, in which the regular
treatment is still iterative transfusions or steroid therapy with their well-known side effects
and the hematopoietic stem cell transplantation the only curative treatment.
References:
1. Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, et al. Diagnosing and treating
Diamond Blackfan anaemia: results of an international clinical consensus conference. British journal of
haematology. 2008 Sep;142(6):859-76.
2. Willig TN, Niemeyer CM, Leblanc T, Tiemann C, Robert A, Budde J, et al. Identification of new
prognosis factors from the clinical and epidemiologic analysis of a registry of 229 Diamond-Blackfan
anemia patients. DBA group of Societe d'Hematologie et d'Immunologie Pediatrique (SHIP), Gesellshaft
fur Padiatrische Onkologie und Hamatologie (GPOH), and the European Society for Pediatric
Hematology and Immunology (ESPHI). Pediatr Res. 1999 Nov;46(5):553-61.
3. Da Costa L, Chanoz-Poulard G, Simansour M, French M, Bouvier R, Prieur F, et al. First de novo
mutation in RPS19 gene as the cause of hydrops fetalis in Diamond-Blackfan anemia. Am J Hematol.
2013 Apr;88(4):340-1.
4. Wlodarski MW, Da Costa L, O'Donohue MF, Gastou M, Karboul N, Montel-Lehry N, et al.
Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-
Blackfan anemia. Haematologica. 2018 Jun;103(6):949-58.
SCIENTIFIC PROGRAMME
SESSION I
BONE MARROW
RESPONSE TO VIRAL
INFECTIONS
SESSION II
HAEMATOLOGICAL
RESPONSE TO SARS
COV2 INFECTION
SESSION III
DYSERYTHROPOIESIS IN
CLONAL HAEMOPOIESIS
AND MDS
SESSION IV
ERYTHROPOIESIS
CONTROL
SESSION V
ERYTHROPOIESIS
CONTROL : PHASE 2
SESSION VI
IRON METABOLISM
AND ERYTHROPOIESIS
SESSION VII
INHERITED
DYSERYTHROPOIESIS
SESSION VIII
GENE THERAPY/EDITION
SESSION IX – DRUGS
AND INEFFECTIVE
ERYTHROPOIESIS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
FACULTY DISCLOSURES