An inherited gain-of-function risk allele in EPOR predisposes to familial JAK2V617F myeloproliferative neoplasms

Graciela Rabadan Moraes; Florence Pasquier; Christophe Marzac; Eric Deconinck; Carlotta Caterina Damanti; Gwendoline Leroy; Mira El-Khoury; Wassim El Nemer; Jean-Jacques Kiladjian; Hana Raslova; Albert Najman; William Vainchenker; Caroline Marty; Christine Bellanné-Chantelot; Isabelle Plo

doi:10.1111/bjh.18165

An inherited gain-of-function risk allele in EPOR predisposes to familial JAK2^V617F myeloproliferative neoplasms

Br J Haematol. 2022 Jul;198(1):131-136. doi: 10.1111/bjh.18165. Epub 2022 Mar 30.

Authors

Graciela Rabadan Moraes^{1

2

3

4}, Florence Pasquier^{1

2

4

5}, Christophe Marzac^{1

2

5

6}, Eric Deconinck⁷, Carlotta Caterina Damanti^{1

2

3

4}, Gwendoline Leroy⁸, Mira El-Khoury^{1

2

3

4}, Wassim El Nemer^{4

9

10

11

12}, Jean-Jacques Kiladjian¹³, Hana Raslova^{1

2

5}, Albert Najman¹⁴, William Vainchenker^{1

2

4

5}, Caroline Marty^{1

2

4

5}, Christine Bellanné-Chantelot^{1

2

8}, Isabelle Plo^{1

2

4

5}

Affiliations

¹ INSERM, UMR1287, Villejuif, France.
² Gustave Roussy, Villejuif, France.
³ INSERM UMR1287, Gustave Roussy, Université de Paris, Villejuif, France.
⁴ Laboratoire d'Excellence GR-Ex, Université Paris Cité, Paris, France.
⁵ INSERM UMR1287, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
⁶ Département d'Hématologie, Gustave Roussy, Villejuif, France.
⁷ Département d'Hématologie, CHU Besançon, Besançon, France.
⁸ Département de Génétique Médicale, AP-HP, Hôpital Pitié Salpêtrière, Sorbonne Université, Paris, France.
⁹ UMR_S1134, BIGR, Inserm, Université de Paris, Paris, France.
¹⁰ Institut National de la Transfusion Sanguine, Paris, France.
¹¹ Etablissement Français du Sang PACA-Corse, Marseille, France.
¹² EFS, CNRS, ADES, 'Biologie des Groupes Sanguins', Aix Marseille University, Marseille, France.
¹³ AP-HP, Saint-Louis Hospital, Paris, France.
¹⁴ Service d'Hématologie Clinique et de Thérapie Cellulaire, AP-HP, Hôpital Saint-Antoine, Sorbonne Université, Paris, France.

PMID: 35355248
DOI: 10.1111/bjh.18165

Abstract

Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPOR^P488S ) in a large family diagnosed with JAK2^V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2^V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPOR^P488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN.

Keywords: EPOR P488S; JAK2 V617F; familial myeloproliferative neoplasms; germline factor; predisposition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Gain of Function Mutation
Humans
Janus Kinase 2 / genetics
Janus Kinase 2 / metabolism
Mutation
Myeloproliferative Disorders* / diagnosis
Myeloproliferative Disorders* / genetics
Polycythemia Vera* / genetics
Receptors, Erythropoietin* / genetics
Thrombocythemia, Essential* / genetics

Substances

Receptors, Erythropoietin
JAK2 protein, human
Janus Kinase 2