MiR-339 promotes development of stem cell leukemia/lymphoma syndrome via downregulation of the BCL2L11 and BAX proapoptotic genes

Tianxiang Hu, Yating Chong, Sumin Lu, Rebecca Wang, Haiyan Qin, Jeane Silva, Eiko Kitamura, Chang Sheng Chang, Lesley Ann Hawthorn, John K. Cowell

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on the promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of the activated FGFR1 kinase on gene transcription, which includes miRNA dysregulation. In a screen for miRNAs that are directly regulated by FGFR1, and which stimulate cell proliferation and survival, we identified miR-339- 5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhances cell survival and inhibition of its function leads to reduced cell viability. miR-339-5p overexpression protects cells from the consequences of FGFR1 inactivation, promoting cell-cycle progression and reduced apoptosis. Transient luciferase reporter assays and qRT-PCR detection of endogenous miR-339-5p expression in stably transduced cell lines demonstrated that BCR-FGFR1 can directly regulate miR- 339-5p expression. This correlation between miR-339-5p and FGFR1 expression is also seen in primary human B-cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the BCL2L11 and BAX genes, which can promote apoptosis. In vivo, SCLL cells forced to overexpress miR-339-5p show amore rapid onset of disease and poorer survival compared with parental cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL shows a significant higher expression of miR339-5p compared with the two cohorts of CLL patient samples, suggesting direct roles in disease progression and supporting the evidence generated in mouse models of SCLL. Significance: Proapoptiotic genes that are direct targets of miR-339-5p significantly influence promotion and aggressive development of leukemia/lymphomas associated with FGFR1 overexpression.

Original languageEnglish (US)
Pages (from-to)3522-3531
Number of pages10
JournalCancer Research
Volume78
Issue number13
DOIs
StatePublished - Jul 1 2018

Fingerprint

Lymphoma
Leukemia
Stem Cells
Down-Regulation
Cell Survival
B-Lymphoid Precursor Cells
Phosphotransferases
Genes
Apoptosis
MicroRNAs
Phenotype
Luciferases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Disease Progression
Cell Cycle
Chromosomes
Cell Proliferation
Cell Line
Polymerase Chain Reaction
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MiR-339 promotes development of stem cell leukemia/lymphoma syndrome via downregulation of the BCL2L11 and BAX proapoptotic genes. / Hu, Tianxiang; Chong, Yating; Lu, Sumin; Wang, Rebecca; Qin, Haiyan; Silva, Jeane; Kitamura, Eiko; Chang, Chang Sheng; Hawthorn, Lesley Ann; Cowell, John K.

In: Cancer Research, Vol. 78, No. 13, 01.07.2018, p. 3522-3531.

Research output: Contribution to journalArticle

Hu, Tianxiang ; Chong, Yating ; Lu, Sumin ; Wang, Rebecca ; Qin, Haiyan ; Silva, Jeane ; Kitamura, Eiko ; Chang, Chang Sheng ; Hawthorn, Lesley Ann ; Cowell, John K. / MiR-339 promotes development of stem cell leukemia/lymphoma syndrome via downregulation of the BCL2L11 and BAX proapoptotic genes. In: Cancer Research. 2018 ; Vol. 78, No. 13. pp. 3522-3531.
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abstract = "The development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on the promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of the activated FGFR1 kinase on gene transcription, which includes miRNA dysregulation. In a screen for miRNAs that are directly regulated by FGFR1, and which stimulate cell proliferation and survival, we identified miR-339- 5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhances cell survival and inhibition of its function leads to reduced cell viability. miR-339-5p overexpression protects cells from the consequences of FGFR1 inactivation, promoting cell-cycle progression and reduced apoptosis. Transient luciferase reporter assays and qRT-PCR detection of endogenous miR-339-5p expression in stably transduced cell lines demonstrated that BCR-FGFR1 can directly regulate miR- 339-5p expression. This correlation between miR-339-5p and FGFR1 expression is also seen in primary human B-cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the BCL2L11 and BAX genes, which can promote apoptosis. In vivo, SCLL cells forced to overexpress miR-339-5p show amore rapid onset of disease and poorer survival compared with parental cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL shows a significant higher expression of miR339-5p compared with the two cohorts of CLL patient samples, suggesting direct roles in disease progression and supporting the evidence generated in mouse models of SCLL. Significance: Proapoptiotic genes that are direct targets of miR-339-5p significantly influence promotion and aggressive development of leukemia/lymphomas associated with FGFR1 overexpression.",
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AU - Hu, Tianxiang

AU - Chong, Yating

AU - Lu, Sumin

AU - Wang, Rebecca

AU - Qin, Haiyan

AU - Silva, Jeane

AU - Kitamura, Eiko

AU - Chang, Chang Sheng

AU - Hawthorn, Lesley Ann

AU - Cowell, John K.

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AB - The development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on the promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of the activated FGFR1 kinase on gene transcription, which includes miRNA dysregulation. In a screen for miRNAs that are directly regulated by FGFR1, and which stimulate cell proliferation and survival, we identified miR-339- 5p, which is highly upregulated in cells carrying various different chimeric kinases. Overexpression of miR-339-5p in SCLL cell types enhances cell survival and inhibition of its function leads to reduced cell viability. miR-339-5p overexpression protects cells from the consequences of FGFR1 inactivation, promoting cell-cycle progression and reduced apoptosis. Transient luciferase reporter assays and qRT-PCR detection of endogenous miR-339-5p expression in stably transduced cell lines demonstrated that BCR-FGFR1 can directly regulate miR- 339-5p expression. This correlation between miR-339-5p and FGFR1 expression is also seen in primary human B-cell precursor acute lymphoblastic leukemia. In a screen to identify targets of miR-339-5p, we identified and verified the BCL2L11 and BAX genes, which can promote apoptosis. In vivo, SCLL cells forced to overexpress miR-339-5p show amore rapid onset of disease and poorer survival compared with parental cells expressing endogenous levels of miR-339-5p. Analysis of human primary B-cell precursor ALL shows a significant higher expression of miR339-5p compared with the two cohorts of CLL patient samples, suggesting direct roles in disease progression and supporting the evidence generated in mouse models of SCLL. Significance: Proapoptiotic genes that are direct targets of miR-339-5p significantly influence promotion and aggressive development of leukemia/lymphomas associated with FGFR1 overexpression.

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