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BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia.

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BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. / Hurtz, Christian; Hatzi, Katerina; Cerchietti, Leandro; Balabanov, Melanie; Park, Eugene; Kim, Yong-mi; Herzog, Sebastian; Ramezani-Rad, Parham; Jumaa, Hassan; Müller, Martin C; Hofmann, Wolf-Karsten; Hochhaus, Andreas; Ye, B Hilda; Agarwal, Anupriya; Druker, Brian J; Shah, Neil P; Melnick, Ari M; Müschen, Markus.

In: J EXP MED, Vol. 208, No. 11, 11, 2011, p. 2163-2174.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Hurtz, C, Hatzi, K, Cerchietti, L, Balabanov, M, Park, E, Kim, Y, Herzog, S, Ramezani-Rad, P, Jumaa, H, Müller, MC, Hofmann, W-K, Hochhaus, A, Ye, BH, Agarwal, A, Druker, BJ, Shah, NP, Melnick, AM & Müschen, M 2011, 'BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia.', J EXP MED, vol. 208, no. 11, 11, pp. 2163-2174. <http://www.ncbi.nlm.nih.gov/pubmed/21911423?dopt=Citation>

APA

Hurtz, C., Hatzi, K., Cerchietti, L., Balabanov, M., Park, E., Kim, Y., Herzog, S., Ramezani-Rad, P., Jumaa, H., Müller, M. C., Hofmann, W-K., Hochhaus, A., Ye, B. H., Agarwal, A., Druker, B. J., Shah, N. P., Melnick, A. M., & Müschen, M. (2011). BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J EXP MED, 208(11), 2163-2174. [11]. http://www.ncbi.nlm.nih.gov/pubmed/21911423?dopt=Citation

Vancouver

Hurtz C, Hatzi K, Cerchietti L, Balabanov M, Park E, Kim Y et al. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J EXP MED. 2011;208(11):2163-2174. 11.

Bibtex

@article{8b93965d04aa4647af4d66224ffb124d,
title = "BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia.",
abstract = "Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34(+) CD38(-) LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs in CML. Clinical validation of this concept could limit the duration of TKI treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation.",
keywords = "Animals, Humans, Disease Models, Animal, Mice, Mice, Knockout, Tumor Cells, Cultured, Neoplasm Transplantation, *Cell Survival, Mice, SCID, Mice, Inbred NOD, Antigens, CD34/metabolism, DNA-Binding Proteins/antagonists & inhibitors/genetics/*metabolism, Forkhead Transcription Factors/metabolism, Hematopoietic Stem Cells/cytology/physiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*pathology/*physiopathology, Neoplastic Stem Cells/*physiology, Piperazines/therapeutic use, Protein Kinase Inhibitors/therapeutic use, Protein-Tyrosine Kinases/antagonists & inhibitors, Pyrimidines/therapeutic use, Tumor Suppressor Protein p53/genetics/*metabolism, Animals, Humans, Disease Models, Animal, Mice, Mice, Knockout, Tumor Cells, Cultured, Neoplasm Transplantation, *Cell Survival, Mice, SCID, Mice, Inbred NOD, Antigens, CD34/metabolism, DNA-Binding Proteins/antagonists & inhibitors/genetics/*metabolism, Forkhead Transcription Factors/metabolism, Hematopoietic Stem Cells/cytology/physiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*pathology/*physiopathology, Neoplastic Stem Cells/*physiology, Piperazines/therapeutic use, Protein Kinase Inhibitors/therapeutic use, Protein-Tyrosine Kinases/antagonists & inhibitors, Pyrimidines/therapeutic use, Tumor Suppressor Protein p53/genetics/*metabolism",
author = "Christian Hurtz and Katerina Hatzi and Leandro Cerchietti and Melanie Balabanov and Eugene Park and Yong-mi Kim and Sebastian Herzog and Parham Ramezani-Rad and Hassan Jumaa and M{\"u}ller, {Martin C} and Wolf-Karsten Hofmann and Andreas Hochhaus and Ye, {B Hilda} and Anupriya Agarwal and Druker, {Brian J} and Shah, {Neil P} and Melnick, {Ari M} and Markus M{\"u}schen",
year = "2011",
language = "English",
volume = "208",
pages = "2163--2174",
journal = "J EXP MED",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "11",

}

RIS

TY - JOUR

T1 - BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia.

AU - Hurtz, Christian

AU - Hatzi, Katerina

AU - Cerchietti, Leandro

AU - Balabanov, Melanie

AU - Park, Eugene

AU - Kim, Yong-mi

AU - Herzog, Sebastian

AU - Ramezani-Rad, Parham

AU - Jumaa, Hassan

AU - Müller, Martin C

AU - Hofmann, Wolf-Karsten

AU - Hochhaus, Andreas

AU - Ye, B Hilda

AU - Agarwal, Anupriya

AU - Druker, Brian J

AU - Shah, Neil P

AU - Melnick, Ari M

AU - Müschen, Markus

PY - 2011

Y1 - 2011

N2 - Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34(+) CD38(-) LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs in CML. Clinical validation of this concept could limit the duration of TKI treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation.

AB - Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34(+) CD38(-) LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs in CML. Clinical validation of this concept could limit the duration of TKI treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation.

KW - Animals

KW - Humans

KW - Disease Models, Animal

KW - Mice

KW - Mice, Knockout

KW - Tumor Cells, Cultured

KW - Neoplasm Transplantation

KW - Cell Survival

KW - Mice, SCID

KW - Mice, Inbred NOD

KW - Antigens, CD34/metabolism

KW - DNA-Binding Proteins/antagonists & inhibitors/genetics/metabolism

KW - Forkhead Transcription Factors/metabolism

KW - Hematopoietic Stem Cells/cytology/physiology

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/pathology/physiopathology

KW - Neoplastic Stem Cells/physiology

KW - Piperazines/therapeutic use

KW - Protein Kinase Inhibitors/therapeutic use

KW - Protein-Tyrosine Kinases/antagonists & inhibitors

KW - Pyrimidines/therapeutic use

KW - Tumor Suppressor Protein p53/genetics/metabolism

KW - Animals

KW - Humans

KW - Disease Models, Animal

KW - Mice

KW - Mice, Knockout

KW - Tumor Cells, Cultured

KW - Neoplasm Transplantation

KW - Cell Survival

KW - Mice, SCID

KW - Mice, Inbred NOD

KW - Antigens, CD34/metabolism

KW - DNA-Binding Proteins/antagonists & inhibitors/genetics/metabolism

KW - Forkhead Transcription Factors/metabolism

KW - Hematopoietic Stem Cells/cytology/physiology

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/pathology/physiopathology

KW - Neoplastic Stem Cells/physiology

KW - Piperazines/therapeutic use

KW - Protein Kinase Inhibitors/therapeutic use

KW - Protein-Tyrosine Kinases/antagonists & inhibitors

KW - Pyrimidines/therapeutic use

KW - Tumor Suppressor Protein p53/genetics/metabolism

M3 - SCORING: Journal article

VL - 208

SP - 2163

EP - 2174

JO - J EXP MED

JF - J EXP MED

SN - 0022-1007

IS - 11

M1 - 11

ER -