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

Cancer Cell. 2015 Mar 9;27(3):409-25. doi: 10.1016/j.ccell.2015.02.003.

Authors

Huimin Geng¹, Christian Hurtz¹, Kyle B Lenz², Zhengshan Chen¹, Dirk Baumjohann³, Sarah Thompson², Natalya A Goloviznina⁴, Wei-Yi Chen⁵, Jianya Huan⁴, Dorian LaTocha⁶, Erica Ballabio⁷, Gang Xiao¹, Jae-Woong Lee¹, Anne Deucher¹, Zhongxia Qi¹, Eugene Park¹, Chuanxin Huang⁸, Rahul Nahar¹, Soo-Mi Kweon¹, Seyedmehdi Shojaee¹, Lai N Chan¹, Jingwei Yu¹, Steven M Kornblau⁹, Janetta J Bijl¹⁰, B Hilda Ye¹¹, K Mark Ansel³, Elisabeth Paietta¹², Ari Melnick⁸, Stephen P Hunger¹³, Peter Kurre⁴, Jeffrey W Tyner¹⁴, Mignon L Loh¹⁵, Robert G Roeder¹⁶, Brian J Druker¹⁷, Jan A Burger⁹, Thomas A Milne⁷, Bill H Chang², Markus Müschen¹⁸

Affiliations

¹ Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
² Division of Pediatric Hematology and Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
³ Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Division of Pediatric Hematology and Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR 97239, USA.
⁵ Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, NY 10065, USA; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
⁶ Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
⁷ MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
⁸ Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
⁹ Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Hôpital Maisonneuve-Rosemont, Montreal, QC H1T 2M4, Canada.
¹¹ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹² Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹³ Division of Pediatric Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹⁴ Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
¹⁵ Pediatric Hematology-Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁶ Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, NY 10065, USA.
¹⁷ Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA; Howard Hughes Medical Institute, Portland, OR 97239, USA.
¹⁸ Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: markus.muschen@ucsf.edu.

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. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR(+) ALL.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Basic Helix-Loop-Helix Transcription Factors / metabolism
Basic Helix-Loop-Helix Transcription Factors / physiology
Clinical Trials as Topic
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
DNA-Binding Proteins / physiology*
Gene Expression Regulation, Neoplastic*
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Molecular Sequence Data
Phosphatidylinositol 3-Kinase / metabolism
Pre-B-Cell Leukemia Transcription Factor 1
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Precursor Cells, B-Lymphoid / metabolism*
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins / physiology
Proto-Oncogene Proteins c-bcl-6
Signal Transduction
Syk Kinase
Up-Regulation
src-Family Kinases / metabolism

Substances

BCL6 protein, human
Basic Helix-Loop-Helix Transcription Factors
DNA-Binding Proteins
Intracellular Signaling Peptides and Proteins
Pre-B-Cell Leukemia Transcription Factor 1
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-6
TCF3 protein, human
PBX1 protein, human
Phosphatidylinositol 3-Kinase
Protein-Tyrosine Kinases
SYK protein, human
Syk Kinase
src-Family Kinases

Associated data

GEO/GSE59332
GEO/GSE59538

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding