A PI3K p110β-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis

Haluk Yuzugullu, Lukas Baitsch, Thanh Von, Allison Steiner, Haoxuan Tong, Jing Ni, Linda K. Clayton, Roderick Bronson, Thomas M. Roberts, Kira Gritsman, Jean J. Zhao

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The tumour suppressor PTEN, which antagonizes PI3K signalling, is frequently inactivated in haematologic malignancies. In mice, deletion of PTEN in haematopoietic stem cells (HSCs) causes perturbed haematopoiesis, myeloproliferative neoplasia (MPN) and leukaemia. Although the roles of the PI3K isoforms have been studied in PTEN-deficient tumours, their individual roles in PTEN-deficient HSCs are unknown. Here we show that when we delete PTEN in HSCs using the Mx1-Cre system, p110β ablation prevents MPN, improves HSC function and suppresses leukaemia initiation. Pharmacologic inhibition of p110β in PTEN-deficient mice recapitulates these genetic findings, but suggests involvement of both Akt-dependent and -independent pathways. Further investigation reveals that a p110β-Rac signalling loop plays a critical role in PTEN-deficient HSCs. Together, these data suggest that myeloid neoplasia driven by PTEN loss is dependent on p110β via p110β-Rac-positive-feedback loop, and that disruption of this loop may offer a new and effective therapeutic strategy for PTEN-deficient leukaemia.

Original languageEnglish (US)
Article number8501
JournalNature Communications
Volume6
DOIs
StatePublished - Oct 7 2015

Fingerprint

hematopoiesis
stem cells
Hematopoiesis
Hematopoietic Stem Cells
Stem cells
Phosphatidylinositol 3-Kinases
leukemias
perturbation
Leukemia
Neoplasms
mice
Tumors
tumors
suppressors
deletion
positive feedback
Hematologic Neoplasms
Ablation
ablation
Protein Isoforms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

A PI3K p110β-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. / Yuzugullu, Haluk; Baitsch, Lukas; Von, Thanh; Steiner, Allison; Tong, Haoxuan; Ni, Jing; Clayton, Linda K.; Bronson, Roderick; Roberts, Thomas M.; Gritsman, Kira; Zhao, Jean J.

In: Nature Communications, Vol. 6, 8501, 07.10.2015.

Research output: Contribution to journalArticle

Yuzugullu, H, Baitsch, L, Von, T, Steiner, A, Tong, H, Ni, J, Clayton, LK, Bronson, R, Roberts, TM, Gritsman, K & Zhao, JJ 2015, 'A PI3K p110β-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis', Nature Communications, vol. 6, 8501. https://doi.org/10.1038/ncomms9501
Yuzugullu, Haluk ; Baitsch, Lukas ; Von, Thanh ; Steiner, Allison ; Tong, Haoxuan ; Ni, Jing ; Clayton, Linda K. ; Bronson, Roderick ; Roberts, Thomas M. ; Gritsman, Kira ; Zhao, Jean J. / A PI3K p110β-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. In: Nature Communications. 2015 ; Vol. 6.
@article{a8247aece5b942bba5d67a7ba87fc93d,
title = "A PI3K p110β-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis",
abstract = "The tumour suppressor PTEN, which antagonizes PI3K signalling, is frequently inactivated in haematologic malignancies. In mice, deletion of PTEN in haematopoietic stem cells (HSCs) causes perturbed haematopoiesis, myeloproliferative neoplasia (MPN) and leukaemia. Although the roles of the PI3K isoforms have been studied in PTEN-deficient tumours, their individual roles in PTEN-deficient HSCs are unknown. Here we show that when we delete PTEN in HSCs using the Mx1-Cre system, p110β ablation prevents MPN, improves HSC function and suppresses leukaemia initiation. Pharmacologic inhibition of p110β in PTEN-deficient mice recapitulates these genetic findings, but suggests involvement of both Akt-dependent and -independent pathways. Further investigation reveals that a p110β-Rac signalling loop plays a critical role in PTEN-deficient HSCs. Together, these data suggest that myeloid neoplasia driven by PTEN loss is dependent on p110β via p110β-Rac-positive-feedback loop, and that disruption of this loop may offer a new and effective therapeutic strategy for PTEN-deficient leukaemia.",
author = "Haluk Yuzugullu and Lukas Baitsch and Thanh Von and Allison Steiner and Haoxuan Tong and Jing Ni and Clayton, {Linda K.} and Roderick Bronson and Roberts, {Thomas M.} and Kira Gritsman and Zhao, {Jean J.}",
year = "2015",
month = "10",
day = "7",
doi = "10.1038/ncomms9501",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - A PI3K p110β-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis

AU - Yuzugullu, Haluk

AU - Baitsch, Lukas

AU - Von, Thanh

AU - Steiner, Allison

AU - Tong, Haoxuan

AU - Ni, Jing

AU - Clayton, Linda K.

AU - Bronson, Roderick

AU - Roberts, Thomas M.

AU - Gritsman, Kira

AU - Zhao, Jean J.

PY - 2015/10/7

Y1 - 2015/10/7

N2 - The tumour suppressor PTEN, which antagonizes PI3K signalling, is frequently inactivated in haematologic malignancies. In mice, deletion of PTEN in haematopoietic stem cells (HSCs) causes perturbed haematopoiesis, myeloproliferative neoplasia (MPN) and leukaemia. Although the roles of the PI3K isoforms have been studied in PTEN-deficient tumours, their individual roles in PTEN-deficient HSCs are unknown. Here we show that when we delete PTEN in HSCs using the Mx1-Cre system, p110β ablation prevents MPN, improves HSC function and suppresses leukaemia initiation. Pharmacologic inhibition of p110β in PTEN-deficient mice recapitulates these genetic findings, but suggests involvement of both Akt-dependent and -independent pathways. Further investigation reveals that a p110β-Rac signalling loop plays a critical role in PTEN-deficient HSCs. Together, these data suggest that myeloid neoplasia driven by PTEN loss is dependent on p110β via p110β-Rac-positive-feedback loop, and that disruption of this loop may offer a new and effective therapeutic strategy for PTEN-deficient leukaemia.

AB - The tumour suppressor PTEN, which antagonizes PI3K signalling, is frequently inactivated in haematologic malignancies. In mice, deletion of PTEN in haematopoietic stem cells (HSCs) causes perturbed haematopoiesis, myeloproliferative neoplasia (MPN) and leukaemia. Although the roles of the PI3K isoforms have been studied in PTEN-deficient tumours, their individual roles in PTEN-deficient HSCs are unknown. Here we show that when we delete PTEN in HSCs using the Mx1-Cre system, p110β ablation prevents MPN, improves HSC function and suppresses leukaemia initiation. Pharmacologic inhibition of p110β in PTEN-deficient mice recapitulates these genetic findings, but suggests involvement of both Akt-dependent and -independent pathways. Further investigation reveals that a p110β-Rac signalling loop plays a critical role in PTEN-deficient HSCs. Together, these data suggest that myeloid neoplasia driven by PTEN loss is dependent on p110β via p110β-Rac-positive-feedback loop, and that disruption of this loop may offer a new and effective therapeutic strategy for PTEN-deficient leukaemia.

UR - http://www.scopus.com/inward/record.url?scp=84943739934&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943739934&partnerID=8YFLogxK

U2 - 10.1038/ncomms9501

DO - 10.1038/ncomms9501

M3 - Article

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 8501

ER -