Myelodysplastic syndromes: SF3B1 mutations..., not like other splicing gene mutations!

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Myelodysplastic syndromes (MDS) are clonal diseases of hematopoietic stem cells. MDS with mutation of the SF3B1 splicing gene, characterized by abnormal erythropoiesis and sideroblastic anemia, are identified by the WHO as diseases with a better prognosis than MDS with mutation of another splicing gene such as SRSF2 or U2AF1.

The Normal and pathological hematopoiesis team (M Fontenay / D Bouscary, Institut Cochin) in collaboration with the Epigenetics, DNA replication and cancer team (B Miotto, Institut Cochin) and the teams of B Palancade (Institut J Monod) and F Chédin (College of Biological Sciences, UC Davis) studied the molecular and functional consequences of SF3B1 mutations, in comparison with those due to other mutations. The researchers show in Nature communications that the genome of erythroblasts from MDS patients with SF3B1 mutation is depleted of transcription intermediates forming DNA:RNA hybrids or R-loops, unlike erythroblasts from MDS patients with SRSF2 or U2AF1 mutation in which the R-loops are in excess inducing genetic instability.

Loss of R-loops in primary erythroblasts with SF3B1 mutation causes tolerable replicative stress associating an acceleration in the rate of progression of DNA replication forks and the formation of single-stranded DNA regions but not double-strand DNA breaks. This replicative stress contributes to the terminal erythroid differentiation defect.

Restoration of R-loops by a histone deacetylase inhibitor reduces replicative stress and improves erythroblast maturation suggesting a therapeutic approach to anemia.


Rombaut D, Lefèvre C, Rached T, Bondu S, Letessier A, Mangione RM, Farhat B, Lesieur-Pasquier A, Castillo-Guzman D, Boussaid I, Friedrich C, Tourville A, De Carvalho M, Levavasseur F, Leduc M, Le Gall M, Battault S, Temple M, Houy A, Bouscary D, Willems L, Park S, Raynaud S, Cluzeau T, Clappier E, Fenaux P, Adès L, Margueron R, Wassef M, Alsafadi S, Chapuis N, Kosmider O, Solary E, Constantinou A, Stern MH, Droin N, Palancade B, Miotto B, Chédin F, Fontenay M. Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation. Nat Commun. 2024 Apr 8;15(1):3016. doi: 10.1038/s41467-024-46547-7. PMID: 38589367.


Michaela Fontenay

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