Interleukin-15 enhances cellular proliferation and up-regulates CNS homing molecules in pre-B acute lymphoblastic leukemia

Mark Williams, Y Yousafzai, C Cox, A Blair, R Carmody, S Sai, KE Chapman, R McAndrew, A Thomas, A Spence, B Gibson, GJ Graham, Christina Halsey

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Genome-wide association studies have consistently implicated the interleukin-15 (IL-15) gene in acute lymphoblastic leukemia (ALL) biology, including associations with disease susceptibility, and increased risk of central nervous system (CNS) involvement. However, whether pre-B ALL blasts directly respond to IL-15 is unknown. Here, we show that most pre-B ALL primary samples and cell lines express IL-15 and components of its receptor and that primary pre-B ALL cells show increased growth in culture in response to IL-15. Investigation of mechanisms of action using IL-15–responsive SD-1 cells shows this growth advantage is maximal under low-serum conditions, mimicking those found in cerebrospinal fluid. IL-15 also upregulates PSGL-1 and CXCR3, molecules associated with CNS trafficking. Investigation of downstream signaling pathways indicates that IL-15 induces signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinase (ERK) 1/2, and to a lesser extent phosphatidylinositol 3-kinase (PI3K) and nuclear factor κB (NF-κB) phosphorylation. The IL-15–mediated growth advantage is abolished by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), PI3K, and NF-κB inhibitors but preserved in the presence of STAT5 inhibition. Together, these observations provide a mechanistic link between increased levels of IL-15 expression and leukemogenesis, high-risk disease, and CNS relapse and suggest potential therapeutic targets.
LanguageEnglish
Pages3116-3127
Number of pages11
JournalBlood
Volume123
Issue number20
DOIs
Publication statusPublished - 15 May 2014
Externally publishedYes

Fingerprint

Interleukin-15
Neurology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Up-Regulation
Central Nervous System
Cell Proliferation
Molecules
STAT5 Transcription Factor
Phosphatidylinositol 3-Kinase
Growth
Genes
Cerebrospinal fluid
Phosphorylation
Mitogen-Activated Protein Kinase 3
Genome-Wide Association Study
Mitogen-Activated Protein Kinase 1
Central Nervous System Diseases
Disease Susceptibility
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases

Keywords

  • lymphoblastic leukemia
  • cerebrospinal fluid

Cite this

Williams, M., Yousafzai, Y., Cox, C., Blair, A., Carmody, R., Sai, S., ... Halsey, C. (2014). Interleukin-15 enhances cellular proliferation and up-regulates CNS homing molecules in pre-B acute lymphoblastic leukemia. Blood, 123(20), 3116-3127. https://doi.org/10.1182/blood-2013-05-499970
Williams, Mark ; Yousafzai, Y ; Cox, C ; Blair, A ; Carmody, R ; Sai, S ; Chapman, KE ; McAndrew, R ; Thomas, A ; Spence, A ; Gibson, B ; Graham, GJ ; Halsey, Christina. / Interleukin-15 enhances cellular proliferation and up-regulates CNS homing molecules in pre-B acute lymphoblastic leukemia. In: Blood. 2014 ; Vol. 123, No. 20. pp. 3116-3127.
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Williams, M, Yousafzai, Y, Cox, C, Blair, A, Carmody, R, Sai, S, Chapman, KE, McAndrew, R, Thomas, A, Spence, A, Gibson, B, Graham, GJ & Halsey, C 2014, 'Interleukin-15 enhances cellular proliferation and up-regulates CNS homing molecules in pre-B acute lymphoblastic leukemia' Blood, vol. 123, no. 20, pp. 3116-3127. https://doi.org/10.1182/blood-2013-05-499970

Interleukin-15 enhances cellular proliferation and up-regulates CNS homing molecules in pre-B acute lymphoblastic leukemia. / Williams, Mark; Yousafzai, Y; Cox, C; Blair, A; Carmody, R; Sai, S; Chapman, KE; McAndrew, R; Thomas, A; Spence, A; Gibson, B; Graham, GJ; Halsey, Christina.

In: Blood, Vol. 123, No. 20, 15.05.2014, p. 3116-3127.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Interleukin-15 enhances cellular proliferation and up-regulates CNS homing molecules in pre-B acute lymphoblastic leukemia

AU - Williams, Mark

AU - Yousafzai, Y

AU - Cox, C

AU - Blair, A

AU - Carmody, R

AU - Sai, S

AU - Chapman, KE

AU - McAndrew, R

AU - Thomas, A

AU - Spence, A

AU - Gibson, B

AU - Graham, GJ

AU - Halsey, Christina

PY - 2014/5/15

Y1 - 2014/5/15

N2 - Genome-wide association studies have consistently implicated the interleukin-15 (IL-15) gene in acute lymphoblastic leukemia (ALL) biology, including associations with disease susceptibility, and increased risk of central nervous system (CNS) involvement. However, whether pre-B ALL blasts directly respond to IL-15 is unknown. Here, we show that most pre-B ALL primary samples and cell lines express IL-15 and components of its receptor and that primary pre-B ALL cells show increased growth in culture in response to IL-15. Investigation of mechanisms of action using IL-15–responsive SD-1 cells shows this growth advantage is maximal under low-serum conditions, mimicking those found in cerebrospinal fluid. IL-15 also upregulates PSGL-1 and CXCR3, molecules associated with CNS trafficking. Investigation of downstream signaling pathways indicates that IL-15 induces signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinase (ERK) 1/2, and to a lesser extent phosphatidylinositol 3-kinase (PI3K) and nuclear factor κB (NF-κB) phosphorylation. The IL-15–mediated growth advantage is abolished by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), PI3K, and NF-κB inhibitors but preserved in the presence of STAT5 inhibition. Together, these observations provide a mechanistic link between increased levels of IL-15 expression and leukemogenesis, high-risk disease, and CNS relapse and suggest potential therapeutic targets.

AB - Genome-wide association studies have consistently implicated the interleukin-15 (IL-15) gene in acute lymphoblastic leukemia (ALL) biology, including associations with disease susceptibility, and increased risk of central nervous system (CNS) involvement. However, whether pre-B ALL blasts directly respond to IL-15 is unknown. Here, we show that most pre-B ALL primary samples and cell lines express IL-15 and components of its receptor and that primary pre-B ALL cells show increased growth in culture in response to IL-15. Investigation of mechanisms of action using IL-15–responsive SD-1 cells shows this growth advantage is maximal under low-serum conditions, mimicking those found in cerebrospinal fluid. IL-15 also upregulates PSGL-1 and CXCR3, molecules associated with CNS trafficking. Investigation of downstream signaling pathways indicates that IL-15 induces signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinase (ERK) 1/2, and to a lesser extent phosphatidylinositol 3-kinase (PI3K) and nuclear factor κB (NF-κB) phosphorylation. The IL-15–mediated growth advantage is abolished by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), PI3K, and NF-κB inhibitors but preserved in the presence of STAT5 inhibition. Together, these observations provide a mechanistic link between increased levels of IL-15 expression and leukemogenesis, high-risk disease, and CNS relapse and suggest potential therapeutic targets.

KW - lymphoblastic leukemia

KW - cerebrospinal fluid

U2 - 10.1182/blood-2013-05-499970

DO - 10.1182/blood-2013-05-499970

M3 - Article

VL - 123

SP - 3116

EP - 3127

JO - Blood

T2 - Blood

JF - Blood

SN - 0006-4971

IS - 20

ER -