2. Academic Validation
  3. Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia

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.
Huimin Geng 1,  Christian Hurtz 1,  Kyle B Lenz 2,  Zhengshan Chen 1,  Dirk Baumjohann 3,  Sarah Thompson 2,  Natalya A Goloviznina 4,  Wei-Yi Chen 5,  Jianya Huan 4,  Dorian LaTocha 6,  Erica Ballabio 7,  Gang Xiao 1,  Jae-Woong Lee 1,  Anne Deucher 1,  Zhongxia Qi 1,  Eugene Park 1,  Chuanxin Huang 8,  Rahul Nahar 1,  Soo-Mi Kweon 1,  Seyedmehdi Shojaee 1,  Lai N Chan 1,  Jingwei Yu 1,  Steven M Kornblau 9,  Janetta J Bijl 10,  B Hilda Ye 11,  K Mark Ansel 3,  Elisabeth Paietta 12,  Ari Melnick 8,  Stephen P Hunger 13,  Peter Kurre 4,  Jeffrey W Tyner 14,  Mignon L Loh 15,  Robert G Roeder 16,  Brian J Druker 17,  Jan A Burger 9,  Thomas A Milne 7,  Bill H Chang 2,  Markus Müschen 18
Affiliations

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: [email protected].
PMID: 25759025 DOI: 10.1016/j.ccell.2015.02.003
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.

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