Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia.

Adult Age Factors Aged Clonal Hematopoiesis / genetics Cytokines / blood Female Humans Interleukin-6 / blood Male Megakaryocytes Middle Aged Mutation Sex Factors Thrombocythemia, Essential / blood Thrombopoietin / blood

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
06 09 2021
Historique:
received: 04 06 2021
accepted: 20 08 2021
entrez: 7 9 2021
pubmed: 8 9 2021
medline: 16 11 2021
Statut: epublish

Résumé

A subset of essential thrombocythemia (ET) cases are negative for disease-defining mutations on JAK2, MPL, and CALR and defined as triple negative (TN). The lack of recurrent mutations in TN-ET patients makes its pathogenesis ambiguous. Here, we screened 483 patients with suspected ET in a single institution, centrally reviewed bone marrow specimens, and identified 23 TN-ET patients. Analysis of clinical records revealed that TN-ET patients were mostly young female, without a history of thrombosis or progression to secondary myelofibrosis and leukemia. Sequencing analysis and human androgen receptor assays revealed that the majority of TN-ET patients exhibited polyclonal hematopoiesis, suggesting a possibility of reactive thrombocytosis in TN-ET. However, the serum levels of thrombopoietin (TPO) and interleukin-6 in TN-ET patients were not significantly different from those in ET patients with canonical mutations and healthy individuals. Rather, CD34-positive cells from TN-ET patients showed a capacity to form megakaryocytic colonies, even in the absence of TPO. No signs of thrombocytosis were observed before TN-ET development, denying the possibility of hereditary thrombocytosis in TN-ET. Overall, these findings indicate that TN-ET is a distinctive disease entity associated with polyclonal hematopoiesis and is paradoxically caused by hematopoietic stem cells harboring a capacity for cell-autonomous megakaryopoiesis.

Identifiants

DOI: 10.1038/s41598-021-97106-9 PMID: 34489506 PMC: PMC8421373
pubmed: 34489506
doi: 10.1038/s41598-021-97106-9
pii: 10.1038/s41598-021-97106-9
pmc: PMC8421373
doi:

Substances chimiques

Cytokines 0
Interleukin-6 0
Thrombopoietin 9014-42-0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

17702

Commentaires et corrections

Type : ErratumIn

Informations de copyright

© 2021. The Author(s).

Références

Vainchenker, W. & Kralovics, R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood 129, 667–679. https://doi.org/10.1182/blood-2016-10-695940 (2017).
doi: 10.1182/blood-2016-10-695940
Tefferi, A. et al. Calreticulin mutations and long-term survival in essential thrombocythemia. Leukemia 28, 2300–2303. https://doi.org/10.1038/leu.2014.148 (2014).
doi: 10.1038/leu.2014.148
Klampfl, T. et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N. Engl. J. Med. 369, 2379–2390. https://doi.org/10.1056/NEJMoa1311347 (2013).
doi: 10.1056/NEJMoa1311347
Nangalia, J. et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N. Engl. J. Med. 369, 2391–2405. https://doi.org/10.1056/NEJMoa1312542 (2013).
doi: 10.1056/NEJMoa1312542 pubmed: 3966280 pmcid: 3966280
Lundberg, P. et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood 123, 2220–2228. https://doi.org/10.1182/blood-2013-11-537167 (2014).
doi: 10.1182/blood-2013-11-537167
Shirane, S. et al. JAK2, CALR, and MPL mutation spectrum in Japanese patients with myeloproliferative neoplasms. Haematologica 100, e46-48. https://doi.org/10.3324/haematol.2014.115113 (2015).
doi: 10.3324/haematol.2014.115113 pubmed: 4803122 pmcid: 4803122
Tefferi, A. et al. 2014 Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 124, 2507–2513. https://doi.org/10.1182/blood-2014-05-579136 (2014) (quiz 2615).
doi: 10.1182/blood-2014-05-579136 pubmed: 4199952 pmcid: 4199952
Fu, R. et al. Analysis of calreticulin mutations in Chinese patients with essential thrombocythemia: Clinical implications in diagnosis, prognosis and treatment. Leukemia 28, 1912–1914. https://doi.org/10.1038/leu.2014.138 (2014).
doi: 10.1038/leu.2014.138
Rotunno, G. et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 123, 1552–1555. https://doi.org/10.1182/blood-2013-11-538983 (2014).
doi: 10.1182/blood-2013-11-538983
Angona, A. et al. Molecular characterisation of triple negative essential thrombocythaemia patients by platelet analysis and targeted sequencing. Blood Cancer J. 6, e463. https://doi.org/10.1038/bcj.2016.75 (2016).
doi: 10.1038/bcj.2016.75 pubmed: 5022184 pmcid: 5022184
Milosevic Feenstra, J. D. et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood 127, 325–332. https://doi.org/10.1182/blood-2015-07-661835 (2016).
doi: 10.1182/blood-2015-07-661835 pubmed: 4752213 pmcid: 4752213
Cabagnols, X. et al. Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients. Blood 127, 333–342. https://doi.org/10.1182/blood-2015-07-661983 (2016).
doi: 10.1182/blood-2015-07-661983
Tefferi, A. et al. Revised cytogenetic risk stratification in primary myelofibrosis: Analysis based on 1002 informative patients. Leukemia 32, 1189–1199. https://doi.org/10.1038/s41375-018-0018-z (2018).
doi: 10.1038/s41375-018-0018-z pubmed: 5940654 pmcid: 5940654
Tonon, L. et al. Unbalanced X-chromosome inactivation in haemopoietic cells from normal women. Br. J. Haematol. 102, 996–1003. https://doi.org/10.1046/j.1365-2141.1998.00867.x (1998).
doi: 10.1046/j.1365-2141.1998.00867.x
Allen, C., Lambert, J. R., Linch, D. C. & Gale, R. E. X chromosome inactivation analysis reveals a difference in the biology of ET patients with JAK2 and CALR mutations. Blood 124, 2091–2093. https://doi.org/10.1182/blood-2014-06-580183 (2014).
doi: 10.1182/blood-2014-06-580183
Uppenkamp, M., Makarova, E., Petrasch, S. & Brittinger, G. Thrombopoietin serum concentration in patients with reactive and myeloproliferative thrombocytosis. Ann. Hematol. 77, 217–223. https://doi.org/10.1007/s002770050446 (1998).
doi: 10.1007/s002770050446
Cerutti, A., Custodi, P., Duranti, M., Noris, P. & Balduini, C. L. Thrombopoietin levels in patients with primary and reactive thrombocytosis. Br. J. Haematol. 99, 281–284. https://doi.org/10.1046/j.1365-2141.1997.3823196.x (1997).
doi: 10.1046/j.1365-2141.1997.3823196.x
Griesshammer, M. et al. High levels of thrombopoietin in sera of patients with essential thrombocythemia: Cause or consequence of abnormal platelet production?. Ann. Hematol. 77, 211–215. https://doi.org/10.1007/s002770050445 (1998).
doi: 10.1007/s002770050445
Panteli, K. E. et al. Serum interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic myeloproliferative diseases. Br. J. Haematol. 130, 709–715. https://doi.org/10.1111/j.1365-2141.2005.05674.x (2005).
doi: 10.1111/j.1365-2141.2005.05674.x
Barbui, T. et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 120, 5128–5133. https://doi.org/10.1182/blood-2012-07-444067 (2012) (quiz 5252).
doi: 10.1182/blood-2012-07-444067
Ju, M. et al. Mutation profiling by targeted sequencing of “triple-negative” essential thrombocythaemia patients. Br. J. Haematol. 181, 857–860. https://doi.org/10.1111/bjh.14723 (2018).
doi: 10.1111/bjh.14723
Ohnishi, K. et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell 156, 663–677. https://doi.org/10.1016/j.cell.2014.01.005 (2014).
doi: 10.1016/j.cell.2014.01.005
Komatsu, N. et al. Megakaryocytopoiesis in vitro of patients with essential thrombocythaemia: Effect of plasma and serum on megakaryocytic colony formation. Br. J. Haematol. 64, 241–252. https://doi.org/10.1111/j.1365-2141.1986.tb04116.x (1986).
doi: 10.1111/j.1365-2141.1986.tb04116.x
Arber, D. A. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127, 2391–2405. https://doi.org/10.1182/blood-2016-03-643544 (2016).
doi: 10.1182/blood-2016-03-643544
Misawa, K. et al. Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms. Int. J. Hematol. 107, 673–680. https://doi.org/10.1007/s12185-018-2421-7 (2018).
doi: 10.1007/s12185-018-2421-7
Edahiro, Y. et al. JAK2V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan. Int. J. Hematol. 99, 625–634. https://doi.org/10.1007/s12185-014-1567-1 (2014).
doi: 10.1007/s12185-014-1567-1
Takei, H. et al. Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay. PLoS ONE 9, e104958. https://doi.org/10.1371/journal.pone.0104958 (2014).
doi: 10.1371/journal.pone.0104958 pubmed: 4140728 pmcid: 4140728
Inano, T. et al. JAK2 exon 12 mutation in myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: Not an exclusive mutation to polycythaemia vera. Br. J. Haematol. 187, e27–e31. https://doi.org/10.1111/bjh.16146 (2019).
doi: 10.1111/bjh.16146
Kawazu, M. et al. Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. PLoS Genet. 13, e1006853. https://doi.org/10.1371/journal.pgen.1006853 (2017).
doi: 10.1371/journal.pgen.1006853 pubmed: 5500377 pmcid: 5500377
Landrum, M. J. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46, D1062–D1067. https://doi.org/10.1093/nar/gkx1153 (2018).
doi: 10.1093/nar/gkx1153
Araki, M. et al. Homomultimerization of mutant calreticulin is a prerequisite for MPL binding and activation. Leukemia 33, 122–131. https://doi.org/10.1038/s41375-018-0181-2 (2019).
doi: 10.1038/s41375-018-0181-2
Wang, Y. et al. Molecular analysis of ovarian mucinous carcinoma reveals different cell of origins. Oncotarget 6, 22949–22958. https://doi.org/10.18632/oncotarget.5146 (2015).
doi: 10.18632/oncotarget.5146 pubmed: 4673211 pmcid: 4673211
Lansdorp, P. M. & Dragowska, W. Long-term erythropoiesis from constant numbers of CD34+ cells in serum-free cultures initiated with highly purified progenitor cells from human bone marrow. J. Exp. Med. 175, 1501–1509. https://doi.org/10.1084/jem.175.6.1501 (1992).
doi: 10.1084/jem.175.6.1501
Hogge, D. et al. Quantitation and characterization of human megakaryocyte colony-forming cells using a standardized serum-free agarose assay. Br. J. Haematol. 96, 790–800. https://doi.org/10.1046/j.1365-2141.1997.d01-2092.x (1997).
doi: 10.1046/j.1365-2141.1997.d01-2092.x

Auteurs

Tadaaki Inano (T)

Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Marito Araki (M)

Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Soji Morishita (S)

Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Misa Imai (M)

Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Yoshihiko Kihara (Y)

Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Maho Okuda (M)

Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Tomioka, Urayasu-city, Chiba, 279-0021, Japan.

Yinjie Yang (Y)

Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Masafumi Ito (M)

Department of Pathology, Japanese Red Cross Nagoya First Hospital, Aichi, Japan.

Satoshi Osaga (S)

Clinical Research Management Center, Nagoya City University Hospital, Aichi, Japan.

Hiroyuki Mano (H)

National Cancer Center Research Institute, Tokyo, Japan.
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Yoko Edahiro (Y)

Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Tomonori Ochiai (T)

Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Kyohei Misawa (K)

Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Yasutaka Fukuda (Y)

Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Jun Ando (J)

Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Norio Komatsu (N)

Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. komatsun@juntendo.ac.jp.
Laboratory for the Development of Therapies against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. komatsun@juntendo.ac.jp.
Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. komatsun@juntendo.ac.jp.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Facteurs âges › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiogiques du sang › Hématopoïèse › Hématopoïèse clonale › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-6 › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système hématopoïétique › Cellules de la moelle osseuse › Mégacaryocytes › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Facteurs sexuels › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Hémopathies et maladies lymphatiques › Hémopathies › Troubles hémorragiques › Thrombocytémie essentielle › Cell-autonomous megakaryopoiesis associated...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Facteurs de croissance hématopoïétique › Facteurs de stimulation des colonies › Thrombopoïétine › Cell-autonomous megakaryopoiesis associated...