January 1, 2023
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: [email protected]. Note that there is a two-week lag in publishing so this issue reflects papers with a PubMed publication date between December 1 through December 15.

Cancer Discovery

BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Panditharatna E, Marques JG, Wang T, Trissal MC, Liu I, Jiang L, Groves A, Dharia NV, Li D,
Hoffman SE, Kugener G, Shaw ML, Mire HM, Hack OA, Dempster JM, Lareau C, Dai L, Sigua LH, Wyatt M, Kalani Z, Goodale A, Vazquez F, Piccioni F, Doench JG, Root DE, Anastas JN, Jones KL, Conway AS, Stopka S, Regan MS, Liang Y, Seo HS, Song K, Bashyal P, Jerome WP, Mathewson ND, Dhe-Paganon S, Suvà ML, Nguyen QD, Ligon KL, Shi Y, Agnihotri S, Agar NYR, Stegmaier K,
Stiles CD, Golub TR, Qi J, Filbin MG

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell-like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas.

SIGNIFICANCE: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1-BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma. See related commentary by Beytagh and Weiss, p. 2730. See related article by Mo et al., p. 2906.

Cancer Discovery

MinimuMM-Seq: Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

Dutta AK, Alberge JB, Lightbody ED, Boehner CJ, Dunford A, Sklavenitis-Pistofidis R, Cowan AN,
Su NK, Horowitz EM, Barr H, Hevenor L, Beckwith JB, Perry J, Cao A, Lin Z, Nadeem O, Stewart C, Getz G, Ghobrial IM

Multiple Myeloma (MM) develops from well-defined precursor stages, however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. We enumerated circulating tumor cells (CTCs) from 261 patients (84 MGUS, 155 SMM, and 22 MM), with neoplastic cells detected in 84%. We developed a novel approach, MinimuMM-seq, which enables detection of translocations and copy number abnormalities through whole-genome sequencing of highly pure CTCs. Application to CTCs in a cohort of 51 patients, 24 with paired BM, was able to detect 100% of clinically reported BM biopsy events and could replace molecular cytogenetics for diagnostic yield and risk classification. Longitudinal sampling of CTCs in 8 patients revealed major clones could be tracked in the blood, with clonal evolution and shifting dynamics of subclones over time. Our findings provide proof of concept that CTC detection and genomic profiling could be used clinically for monitoring and managing disease in MM.

Cancer Discovery
Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia

Uckelmann HJ, Haarer EL, Takeda R, Hatton C, Marinaccio C, Antonissen NJC, Wen Y, Armstrong SA

The dysregulation of developmental and stem cell associated genes is a common phenomenon during cancer development. Around half of acute myeloid leukemia (AML) patients express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncogene mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA Polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small molecule inhibitors produce clinical responses in patients with NPM1-mutated AML.

Elife
Examining the Cooperation Between Extrachromosomal DNA Circles

Zhang J, Zhang CZ
In a departure from previous findings, new results suggest that free-floating pieces of DNA which carry additional copies of cancer-driving genes do not tend to cluster or have increased transcription.

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