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. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR(+) ALL.
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Hurtz
authors.affiliation: 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.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Lenz
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Zhengshan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Baumjohann
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Thompson
authors.affiliation: 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.
authors.forename: Natalya A
authors.initials: NA
authors.lastname: Goloviznina
authors.affiliation: 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.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jianya
authors.initials: J
authors.lastname: Huan
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Dorian
authors.initials: D
authors.lastname: LaTocha
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Erica
authors.initials: E
authors.lastname: Ballabio
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Deucher
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Zhongxia
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.affiliation: Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Huang
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Nahar
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Kweon
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Seyedmehdi
authors.initials: S
authors.lastname: Shojaee
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Lai N
authors.initials: LN
authors.lastname: Chan
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Hôpital Maisonneuve-Rosemont, Montreal, QC H1T 2M4, Canada.
authors.forename: Janetta J
authors.initials: JJ
authors.lastname: Bijl
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: B Hilda
authors.initials: BH
authors.lastname: Ye
authors.affiliation: Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: K Mark
authors.initials: KM
authors.lastname: Ansel
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Division of Pediatric Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Kurre
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA; Department of Cell & Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Pediatric Hematology-Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA; Howard Hughes Medical Institute, Portland, OR 97239, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Milne
authors.affiliation: 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.
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.affiliation: Departments of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: markus.muschen@ucsf.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction; D000072377:Syk Kinase; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D058539:Phosphatidylinositol 3-Kinase; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D000072377:Syk Kinase; D019061:src-Family Kinases; C084103:BCL6 protein, human; C407909:TCF3 protein, human; C083400:PBX1 protein, human; C000606896:SYK protein, human