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C/EBPα induces highly efficient macrophage transdifferentiation of selected B-lymphoma /leukemia cell lines and impairs their tumorigenicity

ABSTRACT: Earlier work demonstrated that the transcription factor C/EBPα can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B-cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPα is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPαER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPα was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPα induction also impaired the cells' tumorigenicity. Likewise, C/EBPα efficiently converted a B- lymphoblastic leukemia cell line into macrophage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced to transdifferentiate by C/EBPα into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy to treat B-cell malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44700 | GEO | 2013/03/14

SECONDARY ACCESSION(S): PRJNA192979

REPOSITORIES: GEO

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C/EBPÎ± induces highly efficient macrophage transdifferentiation of selected B-lymphoma /leukemia cell lines and impairs their tumorigenicity

Project description:Earlier work demonstrated that the transcription factor C/EBPÎ± can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B-cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPÎ± is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPÎ±ER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPÎ± was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPÎ± induction also impaired the cells' tumorigenicity. Likewise, C/EBPÎ± efficiently converted a B- lymphoblastic leukemia cell line into macrophage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced to transdifferentiate by C/EBPÎ± into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy to treat B-cell malignancies. Changes in gene expression during transdifferentiation of BLaER1 cells, comparing uninduced (0h) cells with cells treated with E2 for 3h, 6h, 9h, 12h, 18h, 24h, 36h, 48h, 72h, 120h or 168h. Primary human B-cells and macrophages were used as controls. 2 replicates each.

2013-03-14 | E-GEOD-44700 | biostudies-arrayexpress

Homo sapiens

Project description:C/EBPα induces highly efficient macrophage transdifferentiation of selected B-lymphoma /leukemia cell lines and impairs their tumorigenicity

| PRJNA192979 | ENA

Initiation of MLL-rearranged AML is orchestrated by C/EBPa

Project description:Acute Myeloid Leukemia (AML) is associated with a number of genetic and epigenetic events that result in malignant transformation of hematopoietic cells. In particular, transcription factors essential for normal hematopoiesis and stem cell function are often found mutated leading to the formation of leukemic stem cells and the accumulation of immature blasts. Among them, translocations involving the mixed lineage leukemia (MLL) gene at chromosome band 11q23 are one of the most commonly events (~10 %) and is associated with poor prognosis in human leukemias. Whereas the downstream effects of MLL-fusion proteins are well established, the modes on which these effects are mediated are still unclear and whether MLL-fusion proteins are dependent on other transcriptional regulators or act alone remains elusive. To investigate this we searched gene expression profiles from patients with MLL-rearranged AML compared with normal hematopoietic progenitor cells for transcriptional regulators and found targets of C/EBPα to be up-regulated in the AML samples, suggesting that C/EBPα might collaborate with MLL-fusion proteins in the initial transformation process. We could show that transformation by MLL-fusion proteins is dependent on C/EBPα activity both in early progenitors as well as in GMPs. In contrast, C/EBPα was found to be indispensable in an already established leukemia. These finding led us to study the early transcriptional changes induced by MLL-ENL expression and we identified a combined C/EBPα / MLL-ENL transcriptional signature. Collectivly, our data shows that C/EBPα configure a proper chromatin state required for MLL-fusions to induce malignant transformation. Histone modification profiles (H3K4me3 and H3K27me3) in haematopoietic progenitor cells (preGM, wild type and Cebpa knock out), and C/EBPα binding in GMP cells

2013-12-10 | E-GEOD-47003 | biostudies-arrayexpress

Development of MLL-rearranged leukemia is dependent on a transcriptional program orchestradt by C/EBPα

Project description:Translocations involving the MLL genes are frequently found in Acute Myeloid Leukemia (AML) and are associated with poor prognosis. The MLL fusion proteins act as aberrant transcription factor activating a transcriptional program that transforms the cells, potentially through collaboration with other transcription factors. To investigate this we searched gene expression profiles from patients with MLL-rearranged AML compared with normal hematopoietic progenitor cells for transcriptional regulators and found targets of C/EBPα to be up-regulated in the AML samples, suggesting that C/EBPα might collaborate with MLL fusion proteins in the initial transformation process. We could show that transformation by MLL fusion proteins is dependent on C/EBPα activity both in early progenitors as well as in GMPs. In contrast, C/EBPα was found to be indispensable in an already established leukemia. These results suggest that C/EBPα play an important role in the early transforming event of leukemogenesis. We used microarray to study the early transcriptional changes induced by MLL-ENL expression and we identified a combined C/EBPα / MLL-ENL transcriptional signature. 3 Cebpaflox/flox;Mx1Cre and 3 Cebpaflox/flox;Mx1Cre- mice were sacrificed 14 days after pIpC injection and bone marrow cells were harvested, enriched for cKit-expression and transduced with a pMIG retroviral vector expressing the MLL-ENL fusion protein and GFP. 72 h post first transduction, GFP-positive or negative PreGM cells were sorted.

2013-12-10 | E-GEOD-46534 | biostudies-arrayexpress

circRNA microarray of the Epstein-Barr virus positive Burkitt's lymphoma cell line Akata

Project description:Epstein-Barr virus positive Burkitt's lymphoma cell line Akata (+) and it's EBV-depleted subclone Akata (-) were analyzed for human circRNA expression.

2022-12-19 | GSE206824 | GEO

Sox4 is a key oncogenic target in C/EBPα mutant Acute Myeloid Leukemia

Project description:Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBPα AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemias with a distinct LIC phenotype.

2013-03-23 | GSE45430 | GEO

Naïve human embryonic stem cells can give rise to cells with trophoblast-like transcriptome and methylome [Bisulfite-Seq]

Project description:Human embryonic stem cells (hESCs) readily differentiate to somatic or germ lineages but have impaired ability to form extra-embryonic lineages such as placenta or yolk sac. Here we demonstrate that hESCs cultured in naïve media conditions can be converted into cells that exhibit the cellular and molecular phenotypes of human trophoblast stem cells (hTSCs) derived from human placenta or blastocyst. The resulting “transdifferentiated” hTSCs show reactivation of core placental genes, acquisition of a placenta-like methylome, and the ability to differentiate to extravillous trophoblasts and syncytiotrophoblasts. Modest differences are observed between transdifferentiated and placental hTSCs, most notably in the expression of certain imprinted loci. These results indicate that naïve hESCs can differentiate to extra-embryonic lineage, and demonstrate a new way of modeling human trophoblast specification and placental methylome establishment.

2020-06-16 | GSE150168 | GEO

Naïve human embryonic stem cells can give rise to cells with trophoblast-like transcriptome and methylome [RNA-Seq]

2020-06-16 | GSE152101 | GEO

Development of MLL-rearranged leukemia is dependent on a transcriptional program orchestradt by C/EBPα

2013-12-10 | GSE46534 | GEO

Transcriptional repression of c-Myb and GATA-2 is involved in the effects of C/EBPα in p210 BCR/ABL-expressing cells

Project description:Levels of C/EBPα are low in myeloid blast crisis (BC) of chronic myelogenous leukemia (CML) and its expression in p210BCR/ABL-expressing hematopoietic cells induces granulocytic differentiation, inhibits proliferation and suppresses leukemogenesis. To assess the mechanisms involved in these effects, C/EBPα targets were identified by microarray analyses. Upon C/EBPα activation, expression of c-Myb and GATA-2 was repressed in 32D-BCR/ABL, K562 and CML-BC primary cells but only c-Myb levels decreased slightly in CD34+ normal progenitors. The role of these two genes for the biological effects of C/EBPα was assessed by perturbing their expression in K562 cells. Expression of c-Myb blocked the proliferation inhibition and differentiation-inducing effects of C/EBPα while c-Myb siRNA treatment enhanced C/EBPα-mediated proliferation inhibition and induced changes in gene expression indicative of monocytic differentiation. GATA-2 expression suppressed the proliferation inhibitory effect of C/EBPα but blocked in part the effect on differentiation; GATA-2 siRNA treatment had no effects on C/EBPα induction of differentiation but inhibited proliferation of K562 cells, alone or upon C/EBPα activation. In summary, the effects of C/EBPα in p210BCR/ABL -expressing cells depend, in part, on transcriptional repression of c-Myb and GATA-2. Since perturbation of c-Myb and GATA-2 expression has non identical consequences for proliferation and differentiation of K562 cells, the effects of C/EBPα appear to involve different transcription-regulated targets.

2008-06-13 | GSE11766 | GEO

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