Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core.
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ABSTRACT:
SUBMITTER: Grimm J
PROVIDER: S-EPMC9252908 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We investigated the combination of the irreversible LSD1 inhibitor T-3775440 and the JAK1/JAK2 inhibitor ruxolitinib as novel therapeutic approach in ML-DS which is specifically designed to target key hallmarks of ML-DS leukemogenesis. We observed synergistic anti-leukemic effects by combining both drugs. To elucidate the underlying molecular mechanisms we performed RNAseq in two independent patients samples treated with vehicle, LSD1 inhibitor or ruxolitinib monotherapy or the combination of both drugs.
2022-05-27 | GSE201093 | GEO
Project description:Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core
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Project description:Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.
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Project description:Down syndrome (DS) is the most frequently diagnosed chromosomal disorder of chromosome 21 (HSA21) aneuploidy, characterized by intellectual disability and reduced lifespan. The transcription repressor, Repressor Element-1 Silencing Transcription factor (REST), which acts as an epigenetic regulator, is a crucial regulator of neuronal and glial gene expression. In this study, we identified and investigated the role of REST-target genes in human brain tissues, cerebral organoids, and neural cells in Down syndrome. Gene expression datasets generated from healthy controls and DS samples of human brain tissues, cerebral organoids, NPC, neurons, and astrocytes were retrieved from the Gene Ontology (GEO) and Sequence Read Archive (SRA) databases. Differential expression analysis was performed on all datasets to produce differential expression genes (DEGs) between DS and control groups. REST-targeted DEGs were subjected to functional ontologies, pathways, and network analyses. We found that REST-targeted DEGs in DS were enriched for the JAK-STAT and HIF-1 signaling pathways across multiple distinct brain regions, ages, and neural cell types. We also identified REST-targeted DEGs involved in nervous system development, cell differentiation, fatty acid metabolism and inflammation in the DS brain. Based on the findings, we propose REST as the critical regulator and a promising therapeutic target to modulate homeostatic gene expression in the DS brain.
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Project description:Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2pos DS-ALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2pos, Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.
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Project description:Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γc) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γc cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.
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