Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Functional and Molecular Single-Cell Analyses Implicate PRDM14 in the Initiation of a Novel B-1 Cell Malignancy - Cut and Run experiments

ABSTRACT: Molecular mechanisms underlying high-risk subtypes of leukemia remain elusive. PR domain-containing 14 (Prdm14) is a potent oncogene implicated in the initiation of many cancers, including leukemia. Here, we interrogate the heterogeneity of Prdm14-expressing cell types in a mouse model of T-cell acute lymphoblastic leukemia (T-ALL). We identified an abnormal B-1 cell-like population in pre-leukemic bone marrow. B-1 cells are a self-renewing population of unconventional B cells established during embryonic development. This dataset contains genome-wide profiling of PRDM14, H3K4me1, and H3K4me3 to understand the genome-wide binding of the key TF in the abnormal B1 population and their B-cell conserved and B-1 cell-type specific enhancer and promoter regions. Cut-and-run experiments for each antibody were completed in triplicate, with IgG included as an extra experimental control.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Dustin Sokolowski

PROVIDER: E-MTAB-13159 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:MLL-AF9 expression in normal human umbilical cord blood CD34+ cells leads to long-term proliferation of a myeloid progenitor cell with leukemogenic potential. Expression of a Core Binding Factor leukemia fusion (AML1-ETO or CBFbeta-SMMHC) in human CD34+ cells results in self-renewal of primitive progenitor cells with multilineage potential and stem cell ability, but these cells do not induce leukemia in immunodeficient mice. This comparative microarray study was initiated to determine how faithful these cell cultures are to the transcriptome of patient samples expressing each of these different fusion proteins, and to analyze the signaling pathways that are unique to CBF cultures and MLL-fusion cultures, with the hope of determining why the MLL-fusion cells are leukemogenic while the CBF cells are not. Experiment Overall Design: We have established a culture system whereby we retrovirally transduce human CD34+ cells, obtained from cord blood, with the leukemia fusion genes MLL-AF9 (MA9), AML1-ETO (AE) or CBFbetaMYH11 (CM). Cells expressing each of these fusion proteins are able to proliferate long-term in vitro in a cytokine dependent manner. These cultures resemble somewhat the blast samples from patients that contain these different fusion proteins, in that MA9 cells are predominantly monocytic (M5-like), AE cells have a large population of primitive CD34+ cells with continued abnormal differentiation (M2-like) and CM cells also contain a population of primitive CD34+ cells with continued abnormal differentiation but also have a significant population of abnormal eosinophils (M4Eo). We grow these cells in the presence of fetal bovine serum (FBS), and also grow them in serum-free conditions using the BIT supplement from Stem Cell Technologies. For the current experiments we used cell cultures that had been proliferating in vitro for 8-12 weeks, in either serum-free conditions or with FBS. Replicate samples were included in some instances, and the same clonal cultures that were grown under either BIT or FBS were also included.

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Functional and Molecular Single-Cell Analyses Implicate PRDM14 in the Initiation of a Novel B-1 Cell Malignancy - Cut and Run experiments

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