C/EBP alpha and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor

Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia

The molecular and cellular basis for oncogene collaboration in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is an aggressive malignancy of the bone marrow caused by the uncontrollable proliferation of immature myeloid cells that fail to terminally differentiate. Mutations in AML are acquired hierarchically, where pre-leukaemic mutations are acquired within haematopoietic stem cells (HSCs); while secondary mutations, such as signalling mutations, are acquired within downstream pre-leukaemic progenitor cells. Why certain mutations are pre-leukaemic and thus acquired within the HSCs, compared to others, and the mechanism by which pre-leukaemic and secondary mutations collaborate, are still poorly understood. Utilising knock-in mutant mouse models we showed that HSCs expressing the pre-leukaemic fusion protein Aml1-ETO conferred a competitive advantage. However, activated K-Ras in Aml1-ETO-expressing HSCs had a marked detrimental effect, leading to cell cycle activation and loss of self-renewal associated gene expression. This provides a mechanism for the observed absence of a signalling mutation in pre-malignant HSCs. The specific association between the biallelic CEBPA and zinc finger 1 (ZF1) GATA2 mutations is observed in AML as well as acute erythroid leukaemia (AEL). We show the mutations collaborate to generate a model of AEL with bi-lineage transformation of the myeloid and erythroid lineages. This is due to the biallelic Cebpa mutations reprogramming the neutrophil-monocyte progenitors (NMPs) to acquire ectopic erythroid potential, while the Gata2 mutation synergises with the Cebpa mutations to impair erythroid differentiation progression. The investigation of ZF1 Gata2 mutation in isolation at both heterozygous and homozygous level showed the ZF1 mutation results in loss of Gata2 function only when the mutation is homozygous. As ZF1 GATA2 mutations are heterozygous in patients, this data supports the findings that ZF1 GATA2 and CEBPA mutations must work synergistically to cause leukaemia development.</p

The molecular and cellular basis for oncogene collaboration in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is an aggressive malignancy of the bone marrow caused by the uncontrollable proliferation of immature myeloid cells that fail to terminally differentiate. Mutations in AML are acquired hierarchically, where pre-leukaemic mutations are acquired within haematopoietic stem cells (HSCs); while secondary mutations, such as signalling mutations, are acquired within downstream pre-leukaemic progenitor cells. Why certain mutations are pre-leukaemic and thus acquired within the HSCs, compared to others, and the mechanism by which pre-leukaemic and secondary mutations collaborate, are still poorly understood. Utilising knock-in mutant mouse models we showed that HSCs expressing the pre-leukaemic fusion protein Aml1-ETO conferred a competitive advantage. However, activated K-Ras in Aml1-ETO-expressing HSCs had a marked detrimental effect, leading to cell cycle activation and loss of self-renewal associated gene expression. This provides a mechanism for the observed absence of a signalling mutation in pre-malignant HSCs. The specific association between the biallelic CEBPA and zinc finger 1 (ZF1) GATA2 mutations is observed in AML as well as acute erythroid leukaemia (AEL). We show the mutations collaborate to generate a model of AEL with bi-lineage transformation of the myeloid and erythroid lineages. This is due to the biallelic Cebpa mutations reprogramming the neutrophil-monocyte progenitors (NMPs) to acquire ectopic erythroid potential, while the Gata2 mutation synergises with the Cebpa mutations to impair erythroid differentiation progression. The investigation of ZF1 Gata2 mutation in isolation at both heterozygous and homozygous level showed the ZF1 mutation results in loss of Gata2 function only when the mutation is homozygous. As ZF1 GATA2 mutations are heterozygous in patients, this data supports the findings that ZF1 GATA2 and CEBPA mutations must work synergistically to cause leukaemia development.</p

To bi or not to bi: Acute erythroid leukemias and hematopoietic lineage choice

Acute erythroid leukemia (AEL) is an acute leukemia characterized by erythroid lineage transformation. The WHO 2008 classification recognized two subtypes of AEL: bi-lineage erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia. In the updated 2016 WHO classification the erythroleukemia subtype was removed with around half of cases re-classified as myelodysplastic syndrome (MDS) and half as acute myeloid leukemia (AML). Diagnosis and classification are currently based on morphology using standard blast cutoffs, without integration of underlying genomic and other molecular features. Key outstanding questions are therefore whether AEL can be accurately diagnosed solely based on morphology or whether genetic or other molecular criteria should be included in its classification, and whether considering AEL as an entity distinct from AML and MDS is clinically relevant. We will here discuss recent work on the molecular basis of AEL, including the identification of mutations causative of AEL, and of transcriptional and epigenetic features that can be used to distinguish AEL from MDS and non-erythroid AML, and the prognostic value of these molecular features

Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing

Ageing of the haematopoietic system is accompanied by declining erythropoiesis and lymphopoiesis. Here the authors uncover upregulated IL-6 and TGFβ signalling in aged bone marrow stroma; inhibition of these signals reverses age-related haematopoietic defects, re-balancing haematopoietic stem cell lineage output

Mating competitiveness of Uju.wMel males.

<p>Competitiveness of Uju.wMel males was assessed using three independent replicates of 50 male Uju.wMel : 50 male Uju.wt (<i>w</i>AlbA/B) : 50 females of either Uju.wMel or Uju.wt (total of 300 females in six cages). Hatching embryos indicated a compatible cross where both male and female parents were infected with the same <i>Wolbachia</i>. Error bars show the SEM. No significant differences in male mating competitiveness were found between the two lines with Chi-squared analysis using a likelihood framework.</p

Hatch rate and fecundity of Uju.wMel.

<p>Egg hatch (A) and fecundity or mean number of eggs produced per female per gonotrophic cycle (B) of Uju.wMel was assessed at generation sixteen. Females were blood fed at six days post eclosion, individualized for laying, and eggs hatched after five days. Second instar larvae were counted to calculate percent hatch (A) and eggs per batch per female counted to give fecundity (B). A: Uju.wMel n = 452, UjuT n = 858, Uju.wt n = 508. B: Uju.wMel n = 16, UjuT n = 14, Uju.wt n = 20. Error bars represent the SEM.</p

CHIKV challenge.

<p>Mosquitoes were allowed to feed on artificial blood meals containing virus suspension and 7 days post infection 35–50 females were used for forced salivation. Samples were titrated by focus fluorescent assay on <i>Ae. albopictus</i> C6/36 cells. The transmission rate was estimated as the percentage of mosquitoes with infectious saliva among tested mosquitoes (A). Saliva samples were titrated by focus fluorescent assay on C6/36 <i>Ae. albopictus</i> cell culture. The total number of plaques was counted and the titer was calculated as FFU/saliva (B). No significant difference was found between Uju.wt and UjuT viral titers using a Wilcoxon rank sum test.</p

Geïntegreerde bestrijding trips in freesia in zomer niet eenvoudig: Van der Staaij: "We moeten op zoek naar meer natuurlijke vijanden" (interview met Marieke van der Staaij)

Trips in freesia is niet goed te bestrijden met het huidige middelenpakket. Bovendien wordt het middelenpakket steeds smaller. Door het intensief gebruik van het beperkte aantal middelen is er een groot risico op resistentieontwikkeling. Daarom is er op verzoek van de landelijke commissie een onderzoek gedaan naar de mogelijkheid om trips geïntegreerd te bestrijden met de commercieel beschikbare natuurlijke vijanden en GNO’s