Project description:Classifying leukemias of ambiguous lineage as either acute myeloid leukemia or acute lymphoid leukemia using microRNA expression profiling
Project description:Leukemias with ambiguous lineage comprise a number of loosely defined entities, often without a clear mechanistic basis. Here, we investigated a group of such leukemias with a CpG Island Methylator Phenotype (CIMP), previously identified as CEBPA-silenced AML. Transcriptomics and epigenomics analyses revealed a hybrid myeloid/lymphoid epigenetic landscape, whereas genetic alterations were heterogenous. This suggests that CIMP leukemias are defined by their shared epigenetic profile rather than a common genetic lesion. Gene expression enrichment showed strong similarity with ETP-ALL and an early lymphoid progenitor cell of origin. Accordingly, integration of differential methylation and expression revealed widespread silencing of myeloid transcription factors (TFs), among which CEBPA was key for differentiation arrest. Hypermethylation also resulted in loss of CTCF binding, accompanied by a few changes in chromatin interactions involving critical TFs like KLF4. In conclusion, epigenetic dysregulation, and not genetic lesions, explain the mixed phenotype of a group of CIMP leukemias resembling ETP-ALL.
Project description:IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we performed single-cell RNA-seq on an acute LPS mouse model of lung inflammation to provide insights into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. We identified neutrophils as a source of IL-36 which provides a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
Project description:Many neutrophilic asthma patients do not respond to current medications, highlighting the need for novel therapeutic targets. Here, we investigated the role of intraflagellar transport (IFT) complex protein IFT20 in neutrophilic asthma. Mice lacking CD4+ T cell-specific IFT20 displayed reduced protease-induced neutrophilic asthma inflammation. Thus, IFT20 may represent a promising therapeutic target for treatment of patients with neutrophilic asthma.
Project description:Genome-wide analysis of single nucleotide polymorphisms in 64 acute myeloid leukemias has revealed that 20% exhibited large regions of homozygosity that could not be accounted for by visible chromosomal abnormalities in the karyotype. Further analysis confirmed that these patterns were due to partial uniparental disomy (UPD). Remission bone marrow was available from five patients showing UPD in their leukemias, and in all cases the homozygosity was found to be restricted to the leukemic clone. Two examples of UPD11p were shown to be of different parental origin as indicated by the methylation pattern of the H19 gene. Furthermore, a previously identified homozygous mutation in the CEBPA gene coincided with a large-scale UPD on chromosome 19. These cryptic chromosomal abnormalities, which seem to be nonrandom, have the characteristics of somatic recombination events and may define an important new subclass of leukemia. Patient No. from Table 1 of Raghavan et al 2005 and Sample name Patient No: 1 = Sample name: AML sample 35 diagnosis Patient No: 1 = Sample name: AML sample 107 remission Patient No: 2 = Sample name: AML sample 37 diagnosis Patient No: 3 = Sample name: AML sample 10 diagnosis Patient No: 3 = Sample name: AML sample 44 remission Patient No: 4 = Sample name: AML sample 20 diagnosis Patient No: 5 = Sample name: AML sample 65 diagnosis Patient No: 6 = Sample name: AML sample 69 diagnosis Patient No: 6 = Sample name: AML sample 94 remission Patient No: 7 = Sample name: AML sample 40 diagnosis Patient No: 7 = Sample name: AML sample 41 remission Patient No: 8 = Sample name: AML sample 64 diagnosis Patient No: 9 = Sample name: AML sample 7 diagnosis Patient No: 10 = Sample name: AML sample 49 diagnosis Patient No: 10 = Sample name: AML sample 106 remission Patient No: 11 = Sample name: AML sample 76 diagnosis Patient No: 12 = Sample name: AML sample 79 diagnosis Keywords: DNA copy number, loss of heterozygosity