title: Ibrutinib inhibits pre-BCR+B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK.
abstract: Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR+B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR+ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR+ALL. Consequently, in mouse xenograft models of pre-BCR+ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ALL and highlight the importance of ibrutinib effects on alternative kinase targets.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA.|Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Christian
authors.initials: C
authors.lastname: Hurtz
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Koehrer
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Janssen Research & Development, LLC, Springhouse, PA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Pharmacyclics, Inc., Sunnyvale, CA.
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D010880:Piperidines; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C584409:BLK protein, human; C000625949:BTK protein, human; D019061:src-Family Kinases; D000225:Adenine