Comment on Cancer Cell. 2021 Mar 8;39(3):346-360.e7.

Comment in Cancer Cell. 2021 Mar 8;39(3):301-303.

Author information: (1)Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. (2)Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA. (3)Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA. (4)Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. (5)Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. (6)Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (7)Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA. (8)Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Division of Biostatistics, Department of Public Health Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA. (9)Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, USA. (10)Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. (11)Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (12)Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA. (13)Department of Ophthalmology, Johns Hopkins University, Baltimore, MD 21231, USA. (14)Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA. (15)ESAC, Inc., Rockville, MD 20850, United States. (16)Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA. (17)Leidos Biomedical Research Inc., Frederick NaVonal Laboratory for Cancer Research, Frederick, MD 21702, USA. (18)Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. (19)Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. (20)Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland; International Institute for Molecular Oncology, 60-203 Poznań, Poland. (21)Poznań University of Medical Sciences, 61-701 Poznań, Poland; Institute of Human Genetics Polish Academy of Sciences, 60-479 Poznań, Poland. (22)International Institute for Molecular Oncology, 60-203 Poznań, Poland; Poznań University of Medical Sciences, 61-701 Poznań, Poland. (23)Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (24)Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. (25)Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA. (26)Department of Pathology, Division of Pathology and Laboratory Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA. (27)Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: dchan@jhmi.edu. (28)Department of Pathology and Oncology, Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address: huizhang@jhu.edu. (29)Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bing.zhang@bcm.edu.

Comment in Cancer Cell. 2021 Mar 8;39(3):299-301. Nat Rev Clin Oncol. 2021 Apr;18(4):197-198.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.

Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance.

Author information: (1)University Hospital Zurich, Department of Dermatology, University of Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland. (2)ETH Zurich, Department of Computer Science, Institute of Machine Learning, Universitätstrasse 6, 8092 Zurich, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; University Hospital Zurich, Biomedical Informatics, Schmelzbergstrasse 26, 8006 Zurich, Switzerland. (3)University of Zurich, Department of Quantitative Biomedicine, Winterthurerstrasse 190, 8057 Zurich, Switzerland. (4)SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; ETH Zurich, NEXUS Personalized Health Technologies, John-von-Neumann-Weg 9, 8093 Zurich, Switzerland. (5)University of Zurich, Department of Molecular Life Sciences, Winterthurerstrasse 190, 8057 Zurich, Switzerland. (6)ETH Zurich, Department of Biology, Institute of Molecular Systems Biology, Otto-Stern-Weg 3, 8093 Zurich, Switzerland. (7)ETH Zurich, Department of Health Sciences and Technology, Otto-Stern-Weg 3, 8093 Zurich, Switzerland. (8)University Hospital Basel and University of Basel, Department of Biomedicine, Hebelstrasse 20, 4031 Basel, Switzerland. (9)University Hospital Zurich, Department of Pathology and Molecular Pathology, Schmelzbergstrasse 12, 8091 Zurich, Switzerland. (10)SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; ETH Zurich, Department of Biosystems Science and Engineering, Mattenstrasse 26, 4058 Basel, Switzerland. (11)ETH Zurich, Department of Biosystems Science and Engineering, Mattenstrasse 26, 4058 Basel, Switzerland. (12)University Hospital Zurich, Department of Medical Oncology and Hematology, Rämistrasse 100, 8091 Zurich, Switzerland. (13)Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952 Schlieren, Switzerland. (14)University of Zurich, Department of Quantitative Biomedicine, Winterthurerstrasse 190, 8057 Zurich, Switzerland; ETH Zurich, Institute of Molecular Health Sciences, Otto-Stern-Weg 7, 8093 Zurich, Switzerland. (15)University Hospital Basel and University of Basel, Department of Biomedicine, Hebelstrasse 20, 4031 Basel, Switzerland; University Hospital Basel, Gynecological Cancer Center, Spitalstrasse 21, 4031 Basel, Switzerland. (16)SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; ETH Zurich, Department of Biology, Institute of Molecular Systems Biology, Otto-Stern-Weg 3, 8093 Zurich, Switzerland. (17)University Hospital Basel, Institute of Medical Genetics and Pathology, Schönbeinstrasse 40, 4031 Basel, Switzerland. (18)University Hospital Zurich, Department of Medical Oncology and Hematology, Rämistrasse 100, 8091 Zurich, Switzerland; University of Zurich, Faculty of Medicine, Zurich, Switzerland. (19)ETH Zurich, Department of Computer Science, Institute of Machine Learning, Universitätstrasse 6, 8092 Zurich, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; University Hospital Zurich, Biomedical Informatics, Schmelzbergstrasse 26, 8006 Zurich, Switzerland; ETH Zurich, Department of Biology, Wolfgang-Pauli-Strasse 27, 8093 Zurich, Switzerland. Electronic address: gunnar.raetsch@inf.ethz.ch. (20)University Hospital Zurich, Department of Dermatology, University of Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland. Electronic address: mitchell.levesque@usz.ch.

Comment on Cancer Cell. 2021 Mar 8;39(3):394-406.e4.

At odds with conventional chemotherapeutics, targeted anticancer agents are designed to inhibit precise molecular alterations that support oncogenesis or tumor progression. Despite such an elevated degree of molecular specificity, many clinically employed and experimental targeted anticancer agents also mediate immunostimulatory or immunosuppressive effects that (at least in some settings) influence therapeutic efficacy. Here, we discuss the main immunomodulatory effects of targeted anticancer agents and explore potential avenues to harness them in support of superior clinical efficacy.

Comment on Cancer Cell. 2021 Mar 8;39(3):423-437.e7.

Comment on Nature. 2020 Jan;577(7792):689-694.

CDK4/6 inhibitors have transformed the treatment of metastatic estrogen-receptor-positive HER2-negative breast cancer, with efficacy found consistently for three different inhibitors. Recent adjuvant trials of CDK4/6 inhibitors in early stage breast cancer have produced discordant results, shedding light on their clinical utility and future trial design.

Comment in Cancer Cell. 2021 Mar 8;39(3):297-299.