| Title: |
Study of the mechanism of action of interferon alpha in classical myeloproliferative neoplasms ; Etude du mécanisme d'action de l'interféron alpha dans les néoplasmes myéloprolifératifs classiques |
| Authors: |
Mosca, Matthieu |
| Contributors: |
Hématopoïèse normale et pathologique (U1170 Inserm); Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM); Université Paris Saclay (COmUE); Isabelle Plo; Jean-Luc Villeval |
| Source: |
https://theses.hal.science/tel-02275803 ; Médecine humaine et pathologie. Université Paris Saclay (COmUE), 2018. Français. ⟨NNT : 2018SACLS516⟩. |
| Publisher Information: |
CCSD |
| Publication Year: |
2018 |
| Subject Terms: |
Cellular cycle; Proliferation; Signaling pathway; Prolifération; Néoplasmes myéloprolifératifs; Cycle cellulaire; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Description: |
Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocytemia (ET) and Primary Myelofibrosis (PMF). They are acquired clonal disorders of hematopoietic stem cells (HSC) leading to the hyperplasia of one or several myeloid lineages. They are due to three main recurrent mutations affecting the JAK/STAT signaling pathway: JAK2V617F and mutations in calreticulin (CALR) and thrombopoietin receptor (MPL). Interferon alpha (IFNα) is the only curative treatment that induces not only a hematological response of ET, PV and early MF but also a molecular response both on JAK2V617F or CALR mutated cells. In this study, we wanted to know how and with what kinetics IFN impacts the different mutated hematopoietic compartments. Thus, we have performed a prospective study with a cohort of 50 patients treated by IFNα for 3-5 years. The MPN diseases distribution was 44% ET, 45% PV and 11% MF. This cohort included 33 JAK2V617F-mutated patients, 11 CALR-mutated patients (7 type 1/type 1-like and 4 type 2/type 2-like), 2 both JAK2V617F- and CALR-mutated patients and 1 MPLW515K-mutated patient. At 4-month intervals, the JAK2V617F or/and CALR mutation variant allele frequency was measured in mature cells (granulocytes, platelets). Simultaneously, we have also determined the clonal architecture by studying the presence of the JAK2V617F or CALR mutations in colonies derived from the different hematopoietic stem and progenitor cell (HSPC) populations (CD90+CD34+CD38- HSC-enriched progenitors, CD90-CD34+CD38- immature progenitors and CD90- CD34+CD38+ committed progenitors). After a median follow-up of 30 months, we observed that IFNα targets more efficiently and rapidly the HSPC particularly in HSC-enriched progenitors, than the mature blood cells in JAK2V617F patients (p |
| Document Type: |
doctoral or postdoctoral thesis |
| Language: |
French |
| Relation: |
NNT: 2018SACLS516 |
| Availability: |
https://theses.hal.science/tel-02275803; https://theses.hal.science/tel-02275803v1/document; https://theses.hal.science/tel-02275803v1/file/71111_MOSCA_2018_diffusion.pdf |
| Rights: |
https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.C284A8C6 |
| Database: |
BASE |