Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia

Abstract

The transcription factor encoded by the E-twenty-six (ETS)-related gene, ERG, is an essential regulator of hematopoietic stem cell function and a potent human oncoprotein. Enforced expression of ERG in murine hematopoietic cells leads to the development of a well-characterized lymphoid leukemia and a less well-defined non lymphoid disease. To clarify the latter, we generated murine bone marrow chimeras with enforced Erg expression in engrafted hematopoietic progenitor cells. As expected, these mice developed lymphoid leukemia. However, the previously reported non lymphoid disease that developed was shown to be a uniform, transplantable leukemia with both erythroid and megakaryocytic characteristics. In vivo, this disease had the overall appearance of an erythroleukemia, with an accumulation of immature erythroblasts that infiltrated the bone marrow, spleen, liver, and lung. However, when stimulated in vitro, leukemic cell clones exhibited both erythroid and megakaryocytic differentiation, suggesting that transformation occurred in a bipotential progenitor. Thus, in mice, Erg overexpression induces the development of not only lymphoid leukemia but also erythro-megakaryocytic leukemia.

Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia

“…To validate the role of transposon-mediated activation of Erg in JAK2SB vav leukemia, we demonstrated that TLS-ERG, a human leukemia-derived fusion gene mimicking intragenic insertion within Erg, induced erythroleukemic pathology in recipients of transduced fetal liver cells. These data complement our previous study in which transduction of fetal liver cells with full-length Erg was also found to induce erythro-megakaryocytic leukemia (22). Of interest, unlike full-length Erg, TLS-ERG did not induce development of lymphoid leukemia, and erythro-megakaryocytic leukemia cells from JAK2SB vav mice were found to grow more aggressively in culture than their full-length Erg counterparts.…”

“…The TLS-ERG-induced leukemias, like those in JAK2SB vav mice with Erg and/or Ets1 insertions, were characterized by accumulation of immature erythroid cells, a phenotype also observed in the leukemias driven by full-length Erg (22). Expression of TLS-ERG in human cord blood progenitor cells has been shown to result in a block in erythroid differentiation (23) whereas expression of ERG in K562 cells induces down-regulation of erythroid markers (15), and overexpression of Ets-1 blocks erythroid differentiation in human and mouse hematopoietic progenitor cells (24,25).…”

Differential Requirements of Cellular and Humoral Immune Responses forFv2-Associated Resistance to Erythroleukemia and for Regulation of Retrovirus-Induced Myeloid Leukemia Development

“…The Erg locus was identified in a previous report as a proviral integration site in B6 mice injected as neonates with F-MuLV in association with the development of myeloid leukemia (65). Further, Erg has recently been shown to induce erythro-megakaryocytic leukemia upon hematopoietic cell-specific overexpression (7). Collectively, these data indicate that the erythroleukemia induced with FV in CD4 ϩ T cell-deficient B6 mice is indeed similar to the classical Friend disease in its molecular pathogenesis.…”

Differential Expression of ETS Family Transcription Factors in NCCIT Human Embryonic Carcinoma Cells upon Retinoic Acid-Induced Differentiation

“…9,10,26,27) To facilitate analyses of the expression of ETS transcription factors in NCCIT cells in different states, we divided the ETS factors into 12 subgroups based on the sequences of their ETS DNAbinding domains: PEA3, ESE, ETS, TCF, ELF, TEL, ERG, ERF, SPI, ELG, PDEF, and ER71.…”