The high-mobility group A1a/signal transducer and activator of transcription-3 axis

An achilles heel for hematopoietic malignancies?

Joelle Hillion, Surajit Dhara, Takita Felder Sumter, Mita Mukherjee, Francescopaolo Di Cello, Amy Belton, James Turkson, Souyma Jaganathan, Linzhao Cheng, Zhaohui Ye, Richard Jove, Peter Aplan, Ying Wei Lin, Kelsey Wertzler, Ray Reeves, Ossama Elbahlouh, Jeanne Kowalski, Raka Bhattacharya, Linda M Smith Resar

Research output: Contribution to journalArticle

Abstract

Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a-STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a.

Original languageEnglish (US)
Pages (from-to)10121-10127
Number of pages7
JournalCancer Research
Volume68
Issue number24
DOIs
StatePublished - Dec 15 2008

Fingerprint

STAT3 Transcription Factor
Hematologic Neoplasms
Leukemia
HMGA1b Protein
HMGA1a Protein
Fibroblasts
STAT Transcription Factors
Messenger RNA
Chromatin Immunoprecipitation
Oncogenes
Transcriptome
Transgenic Mice
Genes
Transfection
Lymphoma
Neoplasms
Protein Isoforms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The high-mobility group A1a/signal transducer and activator of transcription-3 axis : An achilles heel for hematopoietic malignancies? / Hillion, Joelle; Dhara, Surajit; Sumter, Takita Felder; Mukherjee, Mita; Di Cello, Francescopaolo; Belton, Amy; Turkson, James; Jaganathan, Souyma; Cheng, Linzhao; Ye, Zhaohui; Jove, Richard; Aplan, Peter; Lin, Ying Wei; Wertzler, Kelsey; Reeves, Ray; Elbahlouh, Ossama; Kowalski, Jeanne; Bhattacharya, Raka; Smith Resar, Linda M.

In: Cancer Research, Vol. 68, No. 24, 15.12.2008, p. 10121-10127.

Research output: Contribution to journalArticle

Hillion, J, Dhara, S, Sumter, TF, Mukherjee, M, Di Cello, F, Belton, A, Turkson, J, Jaganathan, S, Cheng, L, Ye, Z, Jove, R, Aplan, P, Lin, YW, Wertzler, K, Reeves, R, Elbahlouh, O, Kowalski, J, Bhattacharya, R & Smith Resar, LM 2008, 'The high-mobility group A1a/signal transducer and activator of transcription-3 axis: An achilles heel for hematopoietic malignancies?', Cancer Research, vol. 68, no. 24, pp. 10121-10127. https://doi.org/10.1158/0008-5472.CAN-08-2121
Hillion, Joelle ; Dhara, Surajit ; Sumter, Takita Felder ; Mukherjee, Mita ; Di Cello, Francescopaolo ; Belton, Amy ; Turkson, James ; Jaganathan, Souyma ; Cheng, Linzhao ; Ye, Zhaohui ; Jove, Richard ; Aplan, Peter ; Lin, Ying Wei ; Wertzler, Kelsey ; Reeves, Ray ; Elbahlouh, Ossama ; Kowalski, Jeanne ; Bhattacharya, Raka ; Smith Resar, Linda M. / The high-mobility group A1a/signal transducer and activator of transcription-3 axis : An achilles heel for hematopoietic malignancies?. In: Cancer Research. 2008 ; Vol. 68, No. 24. pp. 10121-10127.
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abstract = "Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a-STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a.",
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AU - Dhara, Surajit

AU - Sumter, Takita Felder

AU - Mukherjee, Mita

AU - Di Cello, Francescopaolo

AU - Belton, Amy

AU - Turkson, James

AU - Jaganathan, Souyma

AU - Cheng, Linzhao

AU - Ye, Zhaohui

AU - Jove, Richard

AU - Aplan, Peter

AU - Lin, Ying Wei

AU - Wertzler, Kelsey

AU - Reeves, Ray

AU - Elbahlouh, Ossama

AU - Kowalski, Jeanne

AU - Bhattacharya, Raka

AU - Smith Resar, Linda M

PY - 2008/12/15

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N2 - Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a-STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a.

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