PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

E. G. Garcia; A. Veloso; M. L. Oliveira; J. R. Allen; S. Loontiens; D. Brunson; D. Do; C. Yan; R. Morris; S. Iyer; S. P. Garcia; N. Iftimia; W. Van Loocke; F. Matthijssens; K. McCarthy; J. T. Barata; F. Speleman; T. Taghon; A. Gutierrez; P. Van Vlierberghe; W. Haas; J. S. Blackburn; D. M. Langenau

doi:10.1038/s41375-020-0937-3

PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

E. G. Garcia
, A. Veloso
, M. L. Oliveira
, J. R. Allen
, S. Loontiens
, D. Brunson
, D. Do
, C. Yan
, R. Morris
, S. Iyer
, S. P. Garcia
, N. Iftimia
, W. Van Loocke
, F. Matthijssens
, K. McCarthy
, J. T. Barata
, F. Speleman
, T. Taghon
, A. Gutierrez
, P. Van Vlierberghe

W. Haas, J. S. Blackburn, D. M. Langenau

Molecular and Cellular Biochemistry

Producción científica: Article › revisión exhaustiva

21 Citas (Scopus)

Resumen

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

Idioma original	English
Páginas (desde-hasta)	679-690
Número de páginas	12
Publicación	Leukemia
Volumen	35
N.º	3
DOI	https://doi.org/10.1038/s41375-020-0937-3
Estado	Published - mar 2021

Nota bibliográfica

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Financiación

Acknowledgements We thank Christina Luo, Hiranmayi Ravichan-dran, Rachel Servis, and Ravi Mylvaganam for technical assistance. We thank Drs. Finola Moore and Riadh Lobbardi for helpful discussion and thoughtful review of this manuscript. This work is supported by NIH grant R01CA211734 (DML), R37CA227656 (JSB), CA193651 (AG), the MGH Research Scholar Award (DML), Alex Lemonade Stand Foundation (JSB), the V Foundation for Cancer Research (AG), an Investigatorship from Boston Children’s Hospital (AG), the Research Foundation Flanders (PVV, TT, SL), ‘Kom op tegen Kanker’ (Stand up to Cancer; SL), and the Ghent University Special Research Fund (PVV and TT). Flow cytometry services were supported by MGH Pathology CNY Flow Cytometry Core shared instrumentation grant 1S10RR023440-01A1.

Financiadores	Número del financiador
V Foundation for Cancer Research
JSB
Children's Hospital Boston
Fonds Wetenschappelijk Onderzoek
National Institutes of Health (NIH)
Massachusetts General Hospital
Alex's Lemonade Stand Foundation for Childhood Cancer
European Commission	227656
National Childhood Cancer Registry – National Cancer Institute	K99CA181500, R37CA227656, R01CA193651, R01CA211734
Horizon 2020 Framework Programme	648455
Universiteit Gent	1S10RR023440-01A1
National Center for Research Resources	S10RR023440

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

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10.1038/s41375-020-0937-3

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Garcia, E. G., Veloso, A., Oliveira, M. L., Allen, J. R., Loontiens, S., Brunson, D., Do, D., Yan, C., Morris, R., Iyer, S., Garcia, S. P., Iftimia, N., Van Loocke, W., Matthijssens, F., McCarthy, K., Barata, J. T., Speleman, F., Taghon, T., Gutierrez, A., ... Langenau, D. M. (2021). PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis. Leukemia, 35(3), 679-690. https://doi.org/10.1038/s41375-020-0937-3

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title = "PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis",

abstract = "T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.",

author = "Garcia, \{E. G.\} and A. Veloso and Oliveira, \{M. L.\} and Allen, \{J. R.\} and S. Loontiens and D. Brunson and D. Do and C. Yan and R. Morris and S. Iyer and Garcia, \{S. P.\} and N. Iftimia and \{Van Loocke\}, W. and F. Matthijssens and K. McCarthy and Barata, \{J. T.\} and F. Speleman and T. Taghon and A. Gutierrez and \{Van Vlierberghe\}, P. and W. Haas and Blackburn, \{J. S.\} and Langenau, \{D. M.\}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

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Garcia, EG, Veloso, A, Oliveira, ML, Allen, JR, Loontiens, S, Brunson, D, Do, D, Yan, C, Morris, R, Iyer, S, Garcia, SP, Iftimia, N, Van Loocke, W, Matthijssens, F, McCarthy, K, Barata, JT, Speleman, F, Taghon, T, Gutierrez, A, Van Vlierberghe, P, Haas, W, Blackburn, JS & Langenau, DM 2021, 'PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis', Leukemia, vol. 35, n.º 3, pp. 679-690. https://doi.org/10.1038/s41375-020-0937-3

TY - JOUR

T1 - PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

AU - Garcia, E. G.

AU - Veloso, A.

AU - Oliveira, M. L.

AU - Allen, J. R.

AU - Loontiens, S.

AU - Brunson, D.

AU - Do, D.

AU - Yan, C.

AU - Morris, R.

AU - Iyer, S.

AU - Garcia, S. P.

AU - Iftimia, N.

AU - Van Loocke, W.

AU - Matthijssens, F.

AU - McCarthy, K.

AU - Barata, J. T.

AU - Speleman, F.

AU - Taghon, T.

AU - Gutierrez, A.

AU - Van Vlierberghe, P.

AU - Haas, W.

AU - Blackburn, J. S.

AU - Langenau, D. M.

PY - 2021/3

Y1 - 2021/3

N2 - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

UR - https://www.scopus.com/pages/publications/85087136592

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DO - 10.1038/s41375-020-0937-3

M3 - Article

C2 - 32606318

AN - SCOPUS:85087136592

SN - 0887-6924

VL - 35

SP - 679

EP - 690

JO - Leukemia

JF - Leukemia

IS - 3

ER -

PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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