The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG

The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3' end of the PNT (pointed) domain, in ERG's ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG's interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention

Esrrb conveys naïve pluripotent cells through the formative transcriptional program

Pluripotency is the potential of a single cell to give rise to all embryonic lineages and first emerges in the naïve epiblast of the preimplantation embryo. Upon implantation, epiblast cells transit to a formative phase, which is preparatory for their differentiation into all somatic lineages and primordial germ cells (PGCs). Murine naïve embryonic stem cells (ESCs) recapitulate the molecular and functional properties of the naïve epiblast, including the capacity to acquire a formative state and differentiate. However, the transition to the formative state, and its functional relevance, is still heavily investigated. Here we observed that Esrrb, a pivotal naïve pluripotency factor, is both required and sufficient to activate formative genes. In naïve cells ESRRB occupies both naïve and formative gene loci. During the formative transition, however, ESRRB binding becomes consolidated on formative genes. Subsequently, ESRRB occupancy is mostly lost, and the formative transcriptional program is inactivated. Functionally, genetic inactivation of Esrrb leads to impaired PGC specification, spontaneous expression of mesendoderm and trophectoderm markers, and inability to generate Formative Stem (FS) cells. Moreover, the 3D organisation in a polarised epithelium with a central lumen, as observed in the formative epiblast, is impaired in the absence of Esrrb. Thus, Esrrb is critical for activating the formative transition and consequently for executing timely and unbiased multilineage differentiation and self-organisation of murine pluripotent cells

ETV6-NCOA2 fusion induces T/myeloid mixed-phenotype leukemia through transformation of nonthymic hematopoietic progenitor cells

Mixed-phenotype acute leukemia is a rare subtype of leukemia in which both myeloid and lymphoid markers are co-expressed on the same malignant cells. The pathogenesis is largely unknown, and the treatment is challenging. We previously reported the specific association of the recurrent t(8;12)(q13;p13) chromosomal translocation that creates the ETV6-NCOA2 fusion with T/myeloid leukemias. Here we report that ETV6-NCOA2 initiates T/myeloid leukemia in preclinical models; ectopic expression of ETV6-NCOA2 in mouse bone marrow hematopoietic progenitors induced T/myeloid lymphoma accompanied by spontaneous Notch1-activating mutations. Similarly, cotransduction of human cord blood CD34(+) progenitors with ETV6-NCOA2 and a nontransforming NOTCH1 mutant induced T/myeloid leukemia in immunodeficient mice; the immunophenotype and gene expression pattern were similar to those of patient-derived ETV6-NCOA2 leukemias. Mechanistically, we show that ETV6-NCOA2 forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes. The expression of ETV6-NCOA2 in human and mouse nonthymic hematopoietic progenitor cells induces transcriptional dysregulation, which activates a lymphoid program while failing to repress the expression of myeloid genes such as CSF1 and MEF2C. The ETV6-NCOA2 induced arrest at an early immature T-cell developmental stage. The additional acquisition of activating NOTCH1 mutations transforms the early immature ETV6-NCOA2 cells into T/myeloid leukemias. Here, we describe the first preclinical model to depict the initiation of T/myeloid leukemia by a specific somatic genetic aberration

Cellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsuficiency

Mono-Allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) affecting more than 85% of carriers. How a partial loss of GATA2 functionality enables leukemic transformation occurring years later in life, is unclear. This question is unsolved mainly due to lack of informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different germline Gata2 mutations (tgERG/GATA2het and tgERG/Gata2L359V) accelerate AML in mice expressing the human hematopoietic stem cell regulator ERG. Analysis of ERG/Gata2het fetal liver and bone marrow derived hematopoietic cells revealed a distinct pre-leukemic phenotype. This was characterized by enhanced transition from stem to progenitor state, increased proliferation, and a striking mitochondrial phenotype, consisting of highly expressed Oxidative- Phosphorylation related gene-sets, elevated oxygen consumption rates, and notably, markedly distorted mitochondrial morphology. Importantly, the same mitochondrial gene-expression signature was observed in human AMLs harboring GATA2 aberrations. Similar to the observations in mice, non-leukemic bone marrows from children with germline GATA2 mutation demonstrated marked mitochondrial abnormalities. Thus, we observed the tumor suppressive effects of GATA2 in two germline Gata2 genetic mouse models. As oncogenic mutations often accumulate with age, Gata2 deficiency mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for prevention of leukemic transformation in these patients

Cellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsuficiency.

Mono-Allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) affecting more than 85% of carriers. How a partial loss of GATA2 functionality enables leukemic transformation occurring years later in life, is unclear. This question is unsolved mainly due to lack of informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different germline Gata2 mutations (tgERG/GATA2het and tgERG/Gata2L359V) accelerate AML in mice expressing the human hematopoietic stem cell regulator ERG. Analysis of ERG/Gata2het fetal liver and bone marrow derived hematopoietic cells revealed a distinct pre-leukemic phenotype. This was characterized by enhanced transition from stem to progenitor state, increased proliferation, and a striking mitochondrial phenotype, consisting of highly expressed Oxidative- Phosphorylation related gene-sets, elevated oxygen consumption rates, and notably, markedly distorted mitochondrial morphology. Importantly, the same mitochondrial gene-expression signature was observed in human AMLs harboring GATA2 aberrations. Similar to the observations in mice, non-leukemic bone marrows from children with germline GATA2 mutation demonstrated marked mitochondrial abnormalities. Thus, we observed the tumor suppressive effects of GATA2 in two germline Gata2 genetic mouse models. As oncogenic mutations often accumulate with age, Gata2 deficiency mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for prevention of leukemic transformation in these patients

The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG

Abstract The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3’ end of the PNT (pointed) domain, in ERG’s ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG’s interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention