Longitudinal study of 2 patients with cyclic thrombocytopenia, STAT3 and MPL mutations
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved..
Cyclic thrombocytopenia (CTP) is a rare disease of periodic platelet count oscillations. The pathogenesis of CTP remains elusive. To study the underlying pathophysiology and genetic and cellular associations with CTP, we applied systems biology approaches to 2 patients with stable platelet cycling and reciprocal thrombopoietin (TPO) cycling at multiple time points through 2 cycles. Blood transcriptome analysis revealed cycling of platelet-specific genes, which are in parallel with and precede platelet count oscillation, indicating that cyclical platelet production leads platelet count cycling in both patients. Additionally, neutrophil and erythrocyte-specific genes also showed fluctuations correlating with platelet count changes, consistent with TPO effects on hematopoietic progenitors. Moreover, we found novel genetic associations with CTP. One patient had a novel germline heterozygous loss-of-function (LOF) thrombopoietin receptor (MPL) c.1210G>A mutation, and both had pathogenic somatic gain-of-function (GOF) variants in signal transducer and activator of transcription 3 (STAT3). In addition, both patients had clonal T-cell populations that remained stable throughout platelet count cycles. These mutations and clonal T cells may potentially involve in the pathogenic baseline in these patients, rendering exaggerated persistent thrombopoiesis oscillations of their intrinsic rhythm upon homeostatic perturbations. This work provides new insights into the pathophysiology of CTP and possible therapies.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
|---|---|
| Enthalten in: |
Blood advances - 7(2023), 1 vom: 10. Jan., Seite 190-194 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhang, Haiyu [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
143641-95-6 |
|---|
| Anmerkungen: |
Date Completed 12.01.2023 Date Revised 09.02.2023 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1182/bloodadvances.2021006701 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM339108746 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM339108746 | ||
| 003 | DE-627 | ||
| 005 | 20231226002153.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/bloodadvances.2021006701 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1130.xml |
| 035 | |a (DE-627)NLM339108746 | ||
| 035 | |a (NLM)35381066 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhang, Haiyu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Longitudinal study of 2 patients with cyclic thrombocytopenia, STAT3 and MPL mutations |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.01.2023 | ||
| 500 | |a Date Revised 09.02.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. | ||
| 520 | |a Cyclic thrombocytopenia (CTP) is a rare disease of periodic platelet count oscillations. The pathogenesis of CTP remains elusive. To study the underlying pathophysiology and genetic and cellular associations with CTP, we applied systems biology approaches to 2 patients with stable platelet cycling and reciprocal thrombopoietin (TPO) cycling at multiple time points through 2 cycles. Blood transcriptome analysis revealed cycling of platelet-specific genes, which are in parallel with and precede platelet count oscillation, indicating that cyclical platelet production leads platelet count cycling in both patients. Additionally, neutrophil and erythrocyte-specific genes also showed fluctuations correlating with platelet count changes, consistent with TPO effects on hematopoietic progenitors. Moreover, we found novel genetic associations with CTP. One patient had a novel germline heterozygous loss-of-function (LOF) thrombopoietin receptor (MPL) c.1210G>A mutation, and both had pathogenic somatic gain-of-function (GOF) variants in signal transducer and activator of transcription 3 (STAT3). In addition, both patients had clonal T-cell populations that remained stable throughout platelet count cycles. These mutations and clonal T cells may potentially involve in the pathogenic baseline in these patients, rendering exaggerated persistent thrombopoiesis oscillations of their intrinsic rhythm upon homeostatic perturbations. This work provides new insights into the pathophysiology of CTP and possible therapies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Receptors, Thrombopoietin |2 NLM | |
| 650 | 7 | |a STAT3 Transcription Factor |2 NLM | |
| 650 | 7 | |a MPL protein, human |2 NLM | |
| 650 | 7 | |a 143641-95-6 |2 NLM | |
| 650 | 7 | |a STAT3 protein, human |2 NLM | |
| 700 | 1 | |a Chien, May |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Shomali, William |e verfasserin |4 aut | |
| 700 | 1 | |a Brar, Rondeep S |e verfasserin |4 aut | |
| 700 | 1 | |a Ho, Chandler |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Panpan |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Danfei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Bing M |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Xiangqian |e verfasserin |4 aut | |
| 700 | 1 | |a Tolentino, Lorna L |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Nancy C |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Albert G |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Witteles, Wesley H |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhenping |e verfasserin |4 aut | |
| 700 | 1 | |a Abidi, Parveen |e verfasserin |4 aut | |
| 700 | 1 | |a Jangam, Diwash |e verfasserin |4 aut | |
| 700 | 1 | |a Krieger, Madison S |e verfasserin |4 aut | |
| 700 | 1 | |a Craig, Morgan |e verfasserin |4 aut | |
| 700 | 1 | |a Bussel, James B |e verfasserin |4 aut | |
| 700 | 1 | |a Gotlib, Jason R |e verfasserin |4 aut | |
| 700 | 1 | |a Zehnder, James L |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood advances |d 2016 |g 7(2023), 1 vom: 10. Jan., Seite 190-194 |w (DE-627)NLM268683263 |x 2473-9537 |7 nnns |
| 773 | 1 | 8 | |g volume:7 |g year:2023 |g number:1 |g day:10 |g month:01 |g pages:190-194 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/bloodadvances.2021006701 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 7 |j 2023 |e 1 |b 10 |c 01 |h 190-194 | ||