Growth factor independence 1B (GFI1B) coordinates assembly of transcriptional repressor complexes comprised of corepressors and histone-modifying enzymes to control gene expression programs governing lineage allocation in hematopoiesis. Enforced expression of GFI1B in K562 erythroleukemia cells favors erythroid over megakaryocytic differentiation, providing a platform to define molecular determinants of binary fate decisions triggered by GFI1B. We deployed proteome-wide proximity labeling to identify factors whose inclusion in GFI1B complexes depends upon GFI1B’s obligate effector, lysine-specific demethylase 1 (LSD1). We show that GFI1B preferentially recruits core and putative elements of the BRAF-histone deacetylase (HDAC) (BHC) chromatin-remodeling complex (LSD1, RCOR1, HMG20A, HMG20B, HDAC1, HDAC2, PHF21A, GSE1, ZMYM2, and ZNF217) in an LSD1-dependent manner to control acquisition of erythroid traits by K562 cells. Among these elements, depletion of both HMG20A and HMG20B or of GSE1 blocks GFI1B-mediated erythroid differentiation, phenocopying impaired differentiation brought on by LSD1 depletion or disruption of GFI1B-LSD1 binding. These findings demonstrate the central role of the GFI1B-LSD1 interaction as a determinant of BHC complex recruitment to enable cell fate decisions driven by GFI1B.

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations useable for CHIP detection by performing a data mining analysis of 48 somatic mutation studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with hematologic malignancies. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole exome sequencing data from 4,538 persons belonging to three non-cancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and pre-cancer surveillance for both children and adults.

Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1. Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the five-year follow up of an 18-year-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-week phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. He has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to five years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. While an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study.