Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors

Zhou, Chengjing; Uluisik, Rizvan C; Rowley, Jesse W.; David, Camille; Jones, Courtney L.; Scharer, Christopher D.; Noetzli, Leila; Fisher, Marlie H; Kirkpatrick, Gregory D.; Bark, Katrina; Boss, Jeremy M.; Henry, Curtis J.; Pietras, Eric M.; Paola, Jorge Di; Porter, Christopher C.

doi:10.1016/j.exphem.2022.06.002

Cited by 7 publications

(6 citation statements)

References 63 publications

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“…Previously reported genetically engineered mice harboring a P216L mutation in the endogenous Etv6 allele have normal platelet counts and do not exhibit an overt hematopoietic defect 21 . To investigate this perplexing observation, we introduced wild-type or P216L mETV6 constructs into NIH/3T3 cells for immunofluorescence imaging-based localization analysis (Figure 3A).…”

Section: Resultsmentioning

confidence: 96%

“…Consistently, AlphaFold prediction of the full-length ETV6 structure does not suggest P214 interaction with the ETS or PNT domains (Figure 1A). Furthermore, mice carrying the homologous Etv6 P216L/WT or Etv6 P216L/P216 allele do not exhibit overt hematopoietic defects 21 . These confounding observations have raised questions about the P214L mutation and its role in ETV6 dysfunction and hematologic disease.…”

Section: Introductionmentioning

confidence: 98%

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Enigmatic missense mutations can cause disease via creation ofde novonuclear export signals

McConville,

Thomas,

Beckner

et al. 2024

Preprint

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Disease-causing missense mutations that occur within structurally and functionally unannotated protein regions can guide researchers to new mechanisms of protein regulation and dysfunction. Here, we report that the thrombocytopenia-, myelodysplastic syndromes-, and leukemia-associated P214L mutation in the transcriptional regulator ETV6 creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity. Mechanistic insight inspired the design of humanized ETV6 mice, which we employ to demonstrate that the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance. Beyond ETV6, we employed computational methods to uncover rare disease-associated missense mutations in unrelated proteins that create a nuclear export signal to disrupt protein function. Thus, missense mutations that operate through this mechanism should be predictable and may suggest rational therapeutic strategies for associated diseases.

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Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

Enigmatic missense mutations can cause disease via creation ofde novonuclear export signals

McConville,

Thomas,

Beckner

et al. 2024

Preprint

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“…Competitive transplant experiments revealed Etv6P216L/wt HSPCs had reduced lymphoid reconstitution potential. Specifically, Etv6P216L/wt mice showed impaired MPP4 hematopoietic progenitor populations with lymphoid potential ( 208 ). Transcriptome analysis of the MMP4 population from these mice suggested deregulation of inflammatory pathways as a consequence of the Etv6 variant, however no significant difference in cytokine or chemokines were identified in the BM.…”

Section: Biological Mechanisms Of Bmf And/or Hm Predisposition Tfsmentioning

confidence: 99%

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Zerella,

Homan,

Arts

et al. 2023

Front. Oncol.

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Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.

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“…Studying Etv6 function in murine models is challenging because complete loss of the gene is lethal 21,22 and heterozygous Etv6 mice have obvious unperturbed hematopoiesis 23 . Human induced pluripotent stem cells (iPSC) harboring a pathogenic heterozygous ETV6 mutation do not give rise to an increase in hematopoietic progenitor cells and MK.…”

Section: Introductionmentioning

confidence: 99%

Single-cell analysis of megakaryopoiesis in peripheral CD34+ cells: insights into ETV6-related thrombocytopenia

Bigot

Gabinaud

Hannouche

et al. 2023

Journal of Thrombosis and Haemostasis

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Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors

Cited by 7 publications

References 63 publications

Enigmatic missense mutations can cause disease via creation ofde novonuclear export signals

Enigmatic missense mutations can cause disease via creation ofde novonuclear export signals

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Single-cell analysis of megakaryopoiesis in peripheral CD34+ cells: insights into ETV6-related thrombocytopenia

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