Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia

Huimin Geng; Christian Hurtz; Kyle B. Lenz; Zhengshan Chen; Dirk Baumjohann; Sarah Thompson; Natalya A. Goloviznina; Wei Yi Chen; Jianya Huan; Dorian LaTocha; Erica Ballabio; Gang Xiao; Jae Woong Lee; Anne Deucher; Zhongxia Qi; Eugene Park; Chuanxin Huang; Rahul Nahar; Soo Mi Kweon; Seyedmehdi Shojaee; Lai N. Chan; Jingwei Yu; Steven M. Kornblau; Janetta J. Bijl; B. Hilda Ye; K. Mark Ansel; Elisabeth Paietta; Ari Melnick; Stephen P. Hunger; Peter Kurre; Jeffrey W. Tyner; Mignon L. Loh; Robert G. Roeder; Brian J. Druker; Jan A. Burger; Thomas A. Milne; Bill H. Chang; Markus Müschen

doi:10.1016/j.ccell.2015.02.003

Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia

Huimin Geng, Christian Hurtz, Kyle B. Lenz, Zhengshan Chen, Dirk Baumjohann, Sarah Thompson, Natalya A. Goloviznina, Wei Yi Chen, Jianya Huan, Dorian LaTocha, Erica Ballabio, Gang Xiao, Jae Woong Lee, Anne Deucher, Zhongxia Qi, Eugene Park, Chuanxin Huang, Rahul Nahar, Soo Mi Kweon, Seyedmehdi ShojaeeLai N. Chan, Jingwei Yu, Steven M. Kornblau, Janetta J. Bijl, B. Hilda Ye, K. Mark Ansel, Elisabeth Paietta, Ari Melnick, Stephen P. Hunger, Peter Kurre, Jeffrey W. Tyner, Mignon L. Loh, Robert G. Roeder, Brian J. Druker, Jan A. Burger, Thomas A. Milne, Bill H. Chang, Markus Müschen

Research output: Contribution to journal › Article › peer-review

99 Scopus citations

Abstract

Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR⁺ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. Invivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR⁺ ALL.

Original language	English (US)
Pages (from-to)	409-425
Number of pages	17
Journal	Cancer Cell
Volume	27
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2015.02.003
State	Published - Mar 9 2015

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2015.02.003

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Geng, H., Hurtz, C., Lenz, K. B., Chen, Z., Baumjohann, D., Thompson, S., Goloviznina, N. A., Chen, W. Y., Huan, J., LaTocha, D., Ballabio, E., Xiao, G., Lee, J. W., Deucher, A., Qi, Z., Park, E., Huang, C., Nahar, R., Kweon, S. M., ... Müschen, M. (2015). Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia. Cancer Cell, 27(3), 409-425. https://doi.org/10.1016/j.ccell.2015.02.003

Geng, H, Hurtz, C, Lenz, KB, Chen, Z, Baumjohann, D, Thompson, S, Goloviznina, NA, Chen, WY, Huan, J, LaTocha, D, Ballabio, E, Xiao, G, Lee, JW, Deucher, A, Qi, Z, Park, E, Huang, C, Nahar, R, Kweon, SM, Shojaee, S, Chan, LN, Yu, J, Kornblau, SM, Bijl, JJ, Ye, BH, Mark Ansel, K, Paietta, E, Melnick, A, Hunger, SP, Kurre, P, Tyner, JW, Loh, ML, Roeder, RG, Druker, BJ, Burger, JA, Milne, TA, Chang, BH & Müschen, M 2015, 'Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia', Cancer Cell, vol. 27, no. 3, pp. 409-425. https://doi.org/10.1016/j.ccell.2015.02.003

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title = "Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia",

abstract = "Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. Invivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR+ ALL.",

author = "Huimin Geng and Christian Hurtz and Lenz, {Kyle B.} and Zhengshan Chen and Dirk Baumjohann and Sarah Thompson and Goloviznina, {Natalya A.} and Chen, {Wei Yi} and Jianya Huan and Dorian LaTocha and Erica Ballabio and Gang Xiao and Lee, {Jae Woong} and Anne Deucher and Zhongxia Qi and Eugene Park and Chuanxin Huang and Rahul Nahar and Kweon, {Soo Mi} and Seyedmehdi Shojaee and Chan, {Lai N.} and Jingwei Yu and Kornblau, {Steven M.} and Bijl, {Janetta J.} and Ye, {B. Hilda} and {Mark Ansel}, K. and Elisabeth Paietta and Ari Melnick and Hunger, {Stephen P.} and Peter Kurre and Tyner, {Jeffrey W.} and Loh, {Mignon L.} and Roeder, {Robert G.} and Druker, {Brian J.} and Burger, {Jan A.} and Milne, {Thomas A.} and Chang, {Bill H.} and Markus M{\"u}schen",

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doi = "10.1016/j.ccell.2015.02.003",

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AU - Geng, Huimin

AU - Hurtz, Christian

AU - Lenz, Kyle B.

AU - Chen, Zhengshan

AU - Baumjohann, Dirk

AU - Thompson, Sarah

AU - Goloviznina, Natalya A.

AU - Chen, Wei Yi

AU - Huan, Jianya

AU - LaTocha, Dorian

AU - Ballabio, Erica

AU - Xiao, Gang

AU - Lee, Jae Woong

AU - Deucher, Anne

AU - Qi, Zhongxia

AU - Park, Eugene

AU - Huang, Chuanxin

AU - Nahar, Rahul

AU - Kweon, Soo Mi

AU - Shojaee, Seyedmehdi

AU - Chan, Lai N.

AU - Yu, Jingwei

AU - Kornblau, Steven M.

AU - Bijl, Janetta J.

AU - Ye, B. Hilda

AU - Mark Ansel, K.

AU - Paietta, Elisabeth

AU - Melnick, Ari

AU - Hunger, Stephen P.

AU - Kurre, Peter

AU - Tyner, Jeffrey W.

AU - Loh, Mignon L.

AU - Roeder, Robert G.

AU - Druker, Brian J.

AU - Burger, Jan A.

AU - Milne, Thomas A.

AU - Chang, Bill H.

AU - Müschen, Markus

PY - 2015/3/9

Y1 - 2015/3/9

N2 - Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. Invivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR+ ALL.

AB - Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. Invivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR+ ALL.

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JF - Cancer Cell

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ER -

Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia

Abstract

ASJC Scopus subject areas

UN SDGs

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