ORCID Profile
0000-0002-6880-4895
Current Organisations
The University of Edinburgh
,
University of Cambridge
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Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2023
DOI: 10.1101/2023.01.12.523775
Abstract: Infants and children with MLL-AF4+ leukemia have an urgent need for more efficient and less aggressive therapy. In this study, we studied three microRNAs that are downregulated in MLL-AF4+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL): miR-194, miR-99b and miR-125a-5p. When overexpressed, all three microRNAs impaired the survival of MLL-AF4+ leukemic blasts and the maintenance of MLL-AF4+ BCP-ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in MLL-AF4+ BCP-ALL: CA5B, PPP3CA and PPP2R5C. Using CRISPR-Cas9 and specific inhibitors, we confirmed that CA5B, PPP3CA and PPP2R5C downregulation/inhibition severely compromised the proliferation and survival of MLL-AF4+ leukemic blasts. Importantly, CA5B, PPP3CA and PP2A inhibition by acetazolamide, tacrolimus and LB-100, respectively, showed high toxicity towards MLL-AF4+ leukemic blasts and reduced leukemia burden in vivo . This study highlights how the unique microRNA expression signature of patients with MLL-AF4+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing. There is an urgent need to identify novel therapeutic avenues for patients with MLL-AF4+ BCP-ALL that are more effective and less aggressive. This study identified three clinically available drugs (acetazolamide, tacrolimus and LB-100) with high and selective toxicity towards MLL-AF4+ leukemic cells.
Publisher: Informa UK Limited
Date: 12-2010
DOI: 10.1128/MCB.00870-10
Publisher: Elsevier BV
Date: 05-2011
Publisher: Wiley
Date: 09-2018
Abstract: Increasing evidence suggests that patients with pulmonary arterial hypertension (PAH) demonstrate abnormalities in the bone marrow (BM) and hematopoietic progenitor cells. In addition, PAH is associated with myeloproliferative diseases. We have previously demonstrated that low‐dose lipopolysaccharide (LPS) is a potent stimulus for the development of PAH in the context of a genetic PAH mouse model of BMPR2 dysfunction. We hypothesized that the hematopoietic progenitor cells might be driving disease in this model. To test this hypothesis, we performed adoptive transfer of BM between wild‐type (Ctrl) and heterozygous Bmpr2 null (Mut) mice. Sixteen weeks after BM reconstitution, mice were exposed to low‐dose chronic LPS (0.5 mg/kg three times a week for six weeks). Mice underwent right heart catheterization and tissues were removed for histology. After chronic LPS dosing, Ctrl mice in receipt of Mut BM developed PAH, whereas Mut mice receiving Ctrl BM were protected from PAH. BM histology demonstrated an increase in megakaryocytes and there was an increase in circulating platelets in Ctrl mice receiving Mut BM. These findings demonstrate that the hematopoietic stem cell compartment is involved in the susceptibility to PAH in the Mut mouse. The results raise the possibility that hematopoietic stem cell transplantation might be a potential treatment strategy in genetic forms of PAH.
Publisher: Elsevier BV
Date: 07-2012
Publisher: American Society of Hematology
Date: 02-09-2010
DOI: 10.1182/BLOOD-2009-12-259747
Abstract: The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F–positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2V617F mice develop reduced numbers of lineage−Sca-1+c-Kit+ cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.
Publisher: American Society of Hematology
Date: 21-03-2013
DOI: 10.1182/BLOOD-2012-07-446120
Abstract: The ERG stem cell enhancer is active in acute myeloid leukemia and is regulated by a heptad of transcription factors. Expression signatures derived from ERG promoter–enhancer activity and heptad expression are associated with clinical outcome.
Publisher: Elsevier BV
Date: 10-2021
Publisher: American Society of Hematology
Date: 05-2014
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Katrin Ottersbach.