ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL)

Pearlie K. Epling-Burnette, Fanqi Bai, Sheng Wei, Pratima Chaurasia, Jeffrey S. Painter, Nancy Olashaw, Andrew Hamilton, Said Sebti, Julie Y. Djeu, Thomas P. Loughran

Research output: Contribution to journalArticle

Abstract

Chronic NK lymphoproliferative disease of large granular lymphocytes (LDGL) is characterized by the expansion of activated CD3 -, CD16 + or CD56 + lymphocytes. The mechanism of survival of NK cells from LDGL patients is unknown but may be related to antigenic stimulation. There is currently no standard effective therapy for LDGL, and the disease is characteristically resistant to standard forms of chemotherapy. We found evidence of constitutive activation of extracellular-regulated kinase (ERK) in NK cells from 13/13 patients with NK-LDGL (one patient with aggressive and 12 patients with chronic disease). Ablation of ERK activity by inhibitors or a dominant-negative form of MEK, the upstream activator of ERK, reduced the survival of patient NK cells. Ras was also constitutively active in patient NK cells, and exposure of cells to the Ras inhibitor FTI2153 or to dominant-negative-Ras resulted not only in ERK inhibition but also in enhanced apoptosis in both the presence and absence of anti-Fas. Therefore, we conclude that a constitutively active Ras/MEK/ERK pathway contributes to the accumulation of NK cells in patients with NK-LDGL. These findings suggest that strategies to inhibit this signaling pathway may be useful for the treatment of the NK type of LDGL.

Original languageEnglish (US)
Pages (from-to)9220-9229
Number of pages10
JournalOncogene
Volume23
Issue number57
DOIs
StatePublished - Dec 9 2004

Fingerprint

Large Granular Lymphocytic Leukemia
Natural Killer Cells
Phosphotransferases
Mitogen-Activated Protein Kinase Kinases
Chronic Disease
Lymphocytes
Apoptosis
Drug Therapy
Survival

Keywords

  • Mitogen-activated protein kinase (MAPK)
  • Natural killer cells
  • Ras

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Epling-Burnette, P. K., Bai, F., Wei, S., Chaurasia, P., Painter, J. S., Olashaw, N., ... Loughran, T. P. (2004). ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL). Oncogene, 23(57), 9220-9229. https://doi.org/10.1038/sj.onc.1208122

ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL). / Epling-Burnette, Pearlie K.; Bai, Fanqi; Wei, Sheng; Chaurasia, Pratima; Painter, Jeffrey S.; Olashaw, Nancy; Hamilton, Andrew; Sebti, Said; Djeu, Julie Y.; Loughran, Thomas P.

In: Oncogene, Vol. 23, No. 57, 09.12.2004, p. 9220-9229.

Research output: Contribution to journalArticle

Epling-Burnette, PK, Bai, F, Wei, S, Chaurasia, P, Painter, JS, Olashaw, N, Hamilton, A, Sebti, S, Djeu, JY & Loughran, TP 2004, 'ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL)', Oncogene, vol. 23, no. 57, pp. 9220-9229. https://doi.org/10.1038/sj.onc.1208122
Epling-Burnette, Pearlie K. ; Bai, Fanqi ; Wei, Sheng ; Chaurasia, Pratima ; Painter, Jeffrey S. ; Olashaw, Nancy ; Hamilton, Andrew ; Sebti, Said ; Djeu, Julie Y. ; Loughran, Thomas P. / ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL). In: Oncogene. 2004 ; Vol. 23, No. 57. pp. 9220-9229.
@article{f65962b9e2744c78bacdca88119d617b,
title = "ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL)",
abstract = "Chronic NK lymphoproliferative disease of large granular lymphocytes (LDGL) is characterized by the expansion of activated CD3 -, CD16 + or CD56 + lymphocytes. The mechanism of survival of NK cells from LDGL patients is unknown but may be related to antigenic stimulation. There is currently no standard effective therapy for LDGL, and the disease is characteristically resistant to standard forms of chemotherapy. We found evidence of constitutive activation of extracellular-regulated kinase (ERK) in NK cells from 13/13 patients with NK-LDGL (one patient with aggressive and 12 patients with chronic disease). Ablation of ERK activity by inhibitors or a dominant-negative form of MEK, the upstream activator of ERK, reduced the survival of patient NK cells. Ras was also constitutively active in patient NK cells, and exposure of cells to the Ras inhibitor FTI2153 or to dominant-negative-Ras resulted not only in ERK inhibition but also in enhanced apoptosis in both the presence and absence of anti-Fas. Therefore, we conclude that a constitutively active Ras/MEK/ERK pathway contributes to the accumulation of NK cells in patients with NK-LDGL. These findings suggest that strategies to inhibit this signaling pathway may be useful for the treatment of the NK type of LDGL.",
keywords = "Mitogen-activated protein kinase (MAPK), Natural killer cells, Ras",
author = "Epling-Burnette, {Pearlie K.} and Fanqi Bai and Sheng Wei and Pratima Chaurasia and Painter, {Jeffrey S.} and Nancy Olashaw and Andrew Hamilton and Said Sebti and Djeu, {Julie Y.} and Loughran, {Thomas P.}",
year = "2004",
month = "12",
day = "9",
doi = "10.1038/sj.onc.1208122",
language = "English (US)",
volume = "23",
pages = "9220--9229",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "57",

}

TY - JOUR

T1 - ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL)

AU - Epling-Burnette, Pearlie K.

AU - Bai, Fanqi

AU - Wei, Sheng

AU - Chaurasia, Pratima

AU - Painter, Jeffrey S.

AU - Olashaw, Nancy

AU - Hamilton, Andrew

AU - Sebti, Said

AU - Djeu, Julie Y.

AU - Loughran, Thomas P.

PY - 2004/12/9

Y1 - 2004/12/9

N2 - Chronic NK lymphoproliferative disease of large granular lymphocytes (LDGL) is characterized by the expansion of activated CD3 -, CD16 + or CD56 + lymphocytes. The mechanism of survival of NK cells from LDGL patients is unknown but may be related to antigenic stimulation. There is currently no standard effective therapy for LDGL, and the disease is characteristically resistant to standard forms of chemotherapy. We found evidence of constitutive activation of extracellular-regulated kinase (ERK) in NK cells from 13/13 patients with NK-LDGL (one patient with aggressive and 12 patients with chronic disease). Ablation of ERK activity by inhibitors or a dominant-negative form of MEK, the upstream activator of ERK, reduced the survival of patient NK cells. Ras was also constitutively active in patient NK cells, and exposure of cells to the Ras inhibitor FTI2153 or to dominant-negative-Ras resulted not only in ERK inhibition but also in enhanced apoptosis in both the presence and absence of anti-Fas. Therefore, we conclude that a constitutively active Ras/MEK/ERK pathway contributes to the accumulation of NK cells in patients with NK-LDGL. These findings suggest that strategies to inhibit this signaling pathway may be useful for the treatment of the NK type of LDGL.

AB - Chronic NK lymphoproliferative disease of large granular lymphocytes (LDGL) is characterized by the expansion of activated CD3 -, CD16 + or CD56 + lymphocytes. The mechanism of survival of NK cells from LDGL patients is unknown but may be related to antigenic stimulation. There is currently no standard effective therapy for LDGL, and the disease is characteristically resistant to standard forms of chemotherapy. We found evidence of constitutive activation of extracellular-regulated kinase (ERK) in NK cells from 13/13 patients with NK-LDGL (one patient with aggressive and 12 patients with chronic disease). Ablation of ERK activity by inhibitors or a dominant-negative form of MEK, the upstream activator of ERK, reduced the survival of patient NK cells. Ras was also constitutively active in patient NK cells, and exposure of cells to the Ras inhibitor FTI2153 or to dominant-negative-Ras resulted not only in ERK inhibition but also in enhanced apoptosis in both the presence and absence of anti-Fas. Therefore, we conclude that a constitutively active Ras/MEK/ERK pathway contributes to the accumulation of NK cells in patients with NK-LDGL. These findings suggest that strategies to inhibit this signaling pathway may be useful for the treatment of the NK type of LDGL.

KW - Mitogen-activated protein kinase (MAPK)

KW - Natural killer cells

KW - Ras

UR - http://www.scopus.com/inward/record.url?scp=19944427271&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=19944427271&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1208122

DO - 10.1038/sj.onc.1208122

M3 - Article

C2 - 15516985

AN - SCOPUS:19944427271

VL - 23

SP - 9220

EP - 9229

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 57

ER -