Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia

Mark J. Kiel, Thirunavukkarasu Velusamy, Delphine Rolland, Anagh A. Sahasrabuddhe, Fuzon Chung, Nathanael G. Bailey, Alexandra Schrader, Bo Li, Jun Z. Li, Ayse B. Ozel, Bryan L. Betz, Roberto N. Miranda, L. Jeffrey Medeiros, Lili Zhao, Marco Herling, Megan S. Lim, Kojo S.J. Elenitoba-Johnson

Research output: Contribution to journalArticle

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Abstract

The comprehensive genetic alterations underlying the pathogenesis of T-cell prolym-phocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10, and CHEK2. Strikingly, WGS and/or WES showed largely mutually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0%). Notably, gain-of-function IL2RG mutations are novel and have not been reported in any form of cancer. Further, high-frequency mutations in STAT5B have not been previously reported in T-PLL. Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and activator of transcription 5 (STAT5) hyperactivation, transformed Ba/F3 cells resulting in cytokine-independent growth, and/or enhanced colony formation in Jurkat T cells. Importantly, primary T-PLL cells exhibited constitutive activation of STAT5,andtargeted pharmacologic inhibition ofSTAT5with pimozide induced apoptosis in primary T-PLL cells. These results for the first time provide a portrait of the mutational landscape of T-PLL and implicate deregulation of DNA repair and epigenetic modulators as well as high-frequency mutational activation of the IL2RG-JAK1-JAK3- STAT5B axis in the pathogenesis of T-PLL. These findings offer opportunities for novel targeted therapies in this aggressive leukemia.

Original languageEnglish (US)
Pages (from-to)1460-1472
Number of pages13
JournalBlood
Volume124
Issue number9
DOIs
StatePublished - Aug 28 2014

Fingerprint

T-Cell Prolymphocytic Leukemia
T-cells
Leukemia
T-Lymphocytes
Exome
Genes
STAT5 Transcription Factor
Genome
Mutation
Chemical activation
Pimozide
Jurkat Cells
Deregulation
Mutation Rate
Epigenomics
DNA Repair
Modulators
Repair

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Kiel, M. J., Velusamy, T., Rolland, D., Sahasrabuddhe, A. A., Chung, F., Bailey, N. G., ... Elenitoba-Johnson, K. S. J. (2014). Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood, 124(9), 1460-1472. https://doi.org/10.1182/blood-2014-03-559542

Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. / Kiel, Mark J.; Velusamy, Thirunavukkarasu; Rolland, Delphine; Sahasrabuddhe, Anagh A.; Chung, Fuzon; Bailey, Nathanael G.; Schrader, Alexandra; Li, Bo; Li, Jun Z.; Ozel, Ayse B.; Betz, Bryan L.; Miranda, Roberto N.; Medeiros, L. Jeffrey; Zhao, Lili; Herling, Marco; Lim, Megan S.; Elenitoba-Johnson, Kojo S.J.

In: Blood, Vol. 124, No. 9, 28.08.2014, p. 1460-1472.

Research output: Contribution to journalArticle

Kiel, MJ, Velusamy, T, Rolland, D, Sahasrabuddhe, AA, Chung, F, Bailey, NG, Schrader, A, Li, B, Li, JZ, Ozel, AB, Betz, BL, Miranda, RN, Medeiros, LJ, Zhao, L, Herling, M, Lim, MS & Elenitoba-Johnson, KSJ 2014, 'Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia', Blood, vol. 124, no. 9, pp. 1460-1472. https://doi.org/10.1182/blood-2014-03-559542
Kiel MJ, Velusamy T, Rolland D, Sahasrabuddhe AA, Chung F, Bailey NG et al. Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood. 2014 Aug 28;124(9):1460-1472. https://doi.org/10.1182/blood-2014-03-559542
Kiel, Mark J. ; Velusamy, Thirunavukkarasu ; Rolland, Delphine ; Sahasrabuddhe, Anagh A. ; Chung, Fuzon ; Bailey, Nathanael G. ; Schrader, Alexandra ; Li, Bo ; Li, Jun Z. ; Ozel, Ayse B. ; Betz, Bryan L. ; Miranda, Roberto N. ; Medeiros, L. Jeffrey ; Zhao, Lili ; Herling, Marco ; Lim, Megan S. ; Elenitoba-Johnson, Kojo S.J. / Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. In: Blood. 2014 ; Vol. 124, No. 9. pp. 1460-1472.
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abstract = "The comprehensive genetic alterations underlying the pathogenesis of T-cell prolym-phocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurrently altered genes not previously implicated in T-PLL including EZH2, FBXW10, and CHEK2. Strikingly, WGS and/or WES showed largely mutually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0{\%}). Notably, gain-of-function IL2RG mutations are novel and have not been reported in any form of cancer. Further, high-frequency mutations in STAT5B have not been previously reported in T-PLL. Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and activator of transcription 5 (STAT5) hyperactivation, transformed Ba/F3 cells resulting in cytokine-independent growth, and/or enhanced colony formation in Jurkat T cells. Importantly, primary T-PLL cells exhibited constitutive activation of STAT5,andtargeted pharmacologic inhibition ofSTAT5with pimozide induced apoptosis in primary T-PLL cells. These results for the first time provide a portrait of the mutational landscape of T-PLL and implicate deregulation of DNA repair and epigenetic modulators as well as high-frequency mutational activation of the IL2RG-JAK1-JAK3- STAT5B axis in the pathogenesis of T-PLL. These findings offer opportunities for novel targeted therapies in this aggressive leukemia.",
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AU - Chung, Fuzon

AU - Bailey, Nathanael G.

AU - Schrader, Alexandra

AU - Li, Bo

AU - Li, Jun Z.

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AU - Betz, Bryan L.

AU - Miranda, Roberto N.

AU - Medeiros, L. Jeffrey

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AU - Lim, Megan S.

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