Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia PMID: 25759025

ADC Targets in Oncology

2026-04-10

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

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].

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.