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 & 18 others Lai N. Chan, Jingwei Yu, Steven M. Kornblau, Janetta J. Bijl, B. Hilda Ye, K. Mark Ansel, Elisabeth M. 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 journalArticle

51 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)409-425
Number of pages17
JournalCancer Cell
Volume27
Issue number3
DOIs
StatePublished - Mar 9 2015

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Pre-B Cell Receptors
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Protein-Tyrosine Kinases
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Clinical Trials
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia. / Geng, Huimin; Hurtz, Christian; Lenz, Kyle B.; Chen, Zhengshan; Baumjohann, Dirk; Thompson, Sarah; Goloviznina, Natalya A.; Chen, Wei Yi; Huan, Jianya; LaTocha, Dorian; Ballabio, Erica; Xiao, Gang; Lee, Jae Woong; Deucher, Anne; Qi, Zhongxia; Park, Eugene; Huang, Chuanxin; Nahar, Rahul; Kweon, Soo Mi; Shojaee, Seyedmehdi; Chan, Lai N.; Yu, Jingwei; Kornblau, Steven M.; Bijl, Janetta J.; Ye, B. Hilda; Mark Ansel, K.; Paietta, Elisabeth M.; Melnick, Ari; Hunger, Stephen P.; Kurre, Peter; Tyner, Jeffrey W.; Loh, Mignon L.; Roeder, Robert G.; Druker, Brian J.; Burger, Jan A.; Milne, Thomas A.; Chang, Bill H.; Müschen, Markus.

In: Cancer Cell, Vol. 27, No. 3, 09.03.2015, p. 409-425.

Research output: Contribution to journalArticle

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, EM, 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
Geng, Huimin ; Hurtz, Christian ; Lenz, Kyle B. ; Chen, Zhengshan ; Baumjohann, Dirk ; Thompson, Sarah ; Goloviznina, Natalya A. ; Chen, Wei Yi ; Huan, Jianya ; LaTocha, Dorian ; Ballabio, Erica ; Xiao, Gang ; Lee, Jae Woong ; Deucher, Anne ; Qi, Zhongxia ; Park, Eugene ; Huang, Chuanxin ; Nahar, Rahul ; Kweon, Soo Mi ; Shojaee, Seyedmehdi ; Chan, Lai N. ; Yu, Jingwei ; Kornblau, Steven M. ; Bijl, Janetta J. ; Ye, B. Hilda ; Mark Ansel, K. ; Paietta, Elisabeth M. ; Melnick, Ari ; Hunger, Stephen P. ; Kurre, Peter ; Tyner, Jeffrey W. ; Loh, Mignon L. ; Roeder, Robert G. ; Druker, Brian J. ; Burger, Jan A. ; Milne, Thomas A. ; Chang, Bill H. ; Müschen, Markus. / Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia. In: Cancer Cell. 2015 ; Vol. 27, No. 3. pp. 409-425.
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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.",
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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 M.

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

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