SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia.
Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.
1] UMR_S745 INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes Sorbonne Paris Cité, Paris, France [2] Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
E
E
Pasmant
Service de Génétique, C.H.U. de Poitiers, Poitiers, France.
B
B
Gilbert-Dussardier
1] Service d'Hématologie-Oncologie, Hôpital A Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France [2] Université Pierre et Marie Curie Paris 6, Paris, France [3] UMR938, Université Paris 6, Pierre et Marie Curie, Paris, France.
A
0000000183631622
A
Petit
INSERM 1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Paris, France.
B
B
de Laval
1] UMR_S745 INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes Sorbonne Paris Cité, Paris, France [2] Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
A
A
Luscan
UMR_S745 INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
A
A
Gruber
1] UMR938, Université Paris 6, Pierre et Marie Curie, Paris, France [2] Service d'Hématologie Biologique, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France.
H
H
Lapillonne
1] Service d'Hématologie-Oncologie, Hôpital A Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France [2] Université Pierre et Marie Curie Paris 6, Paris, France [3] UMR938, Université Paris 6, Pierre et Marie Curie, Paris, France.
C
C
Deswarte
Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
P
P
Goussard
UMR_S745 INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
I
I
Laurendeau
UMR967, CEA, Université Paris 7, Fontenay aux Roses, France.
B
B
Uzan
UMR967, CEA, Université Paris 7, Fontenay aux Roses, France.
F
F
Pflumio
Laboratoire d'Hématologie Biologique, C.H.U. de Poitiers, Poitiers, France.
F
F
Brizard
Service de Dermatologie, C.H.U. de Dijon et EA 4271, Université de Bourgogne, France.
P
P
Vabres
UMR967, CEA, Université Paris 7, Fontenay aux Roses, France.
I
I
Naguibvena
1] Service d'Hématologie-Oncologie, Hôpital A Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France [2] Université Pierre et Marie Curie Paris 6, Paris, France.
S
S
Fasola
Service de Pédiatrie, C.H.U de Poitiers, Poitiers, France.
F
F
Millot
INSERM 1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Paris, France.
F
F
Porteu
1] UMR_S745 INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes Sorbonne Paris Cité, Paris, France [2] Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France [3] Service de Génétique, C.H.U. de Poitiers, Poitiers, France.
D
D
Vidaud
1] Service d'Hématologie-Oncologie, Hôpital A Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France [2] Université Pierre et Marie Curie Paris 6, Paris, France [3] UMR938, Université Paris 6, Pierre et Marie Curie, Paris, France.
J
J
Landman-Parker
Service d'Hématologie Biologique, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France.
P
P
Ballerini
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D019080:Cafe-au-Lait Spots / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000235:genetics* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D025542:Neurofibromin 1; C504812:SPRED1 protein, human