Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression analysis of WT and Flt3-ITD multipotent progenitors

ABSTRACT: FLT3-ITDs Introduce a Myeloid Differentiation and Transformation Bias in Lympho-myeloid Multipotent Progenitors WT multipotent progenitors were compared with FLT3-ITD multipotent progenitors

ORGANISM(S): Mus musculus

SUBMITTER: Sten Eirik Jacobsen

PROVIDER: E-GEOD-35805 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors.

Mead Adam J AJ Kharazi Shabnam S Atkinson Deborah D Macaulay Iain I Pecquet Christian C Loughran Stephen S Lutteropp Michael M Woll Petter P Chowdhury Onima O Luc Sidinh S Buza-Vidas Natalija N Ferry Helen H Clark Sally-Ann SA Goardon Nicolas N Vyas Paresh P Constantinescu Stefan N SN Sitnicka Ewa E Nerlov Claus C Jacobsen Sten Eirik W SE

Cell reports 20130530 6

Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that we ...[more]

PMID: 23727242

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Project description:Autotaxin (ATX) has been reported to act as a motility and growth factor in a variety of cancer cells. The ATX protein acts as a secreted lysophospholipase D (lysoPLD) by converting lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which signals via G-protein coupled receptors and has important functions in cell migration and proliferation. The current study demonstrates that ATX expression is upregulated and functionally active in FLT3-ITD+ human blasts. ATX expression was also found in normal human CD34+ progenitor cells and selected myeloid and lymphoid subpopulations. Stable transduction of mutant FLT3-ITD increased ATX mRNA in selected cell lines, whereas inhibition of FLT3-ITD signaling by sublethal doses of PKC412 led to a significant down-regulation of ATX. Moreover, results indicate that the Jun N-terminal kinase (JNK) is an important mediator between FLT3 signaling and ATX. In the presence of LPC, ATX expression led to a significant increase of proliferation. LPA caused proliferation of all tested cell lines, regardless of ATX expression and induced chemotaxis in human leukemic cell lines and human CD34+ progenitors. LPC increased chemotaxis, in cells with high expression of endogenous and exogenous ATX, by at least 80% demonstrating the autocrine effect of ATX expression. Inhibition of ATX using a small molecule inhibitor induced selective killing of ATX-expressing cell lines and reduced the motile phenotype observed in this cells. Our data suggest that the production of bioactive LPA through ATX is involved in controlling proliferation and migration during hematopoiesis and that deregulation contributes to the pathogenesis of AML. AML Classes: Molecular/cytogenetic group of acute myeloid leukemia, either internal tandem duplication (FLT3) or FLT3 point mutation (D835) or normal karyotype (NK) or t(8;21) transclocation (t821) or monosomy 7 (mono7) or inversion on chromosome 16 (inv16) or high leukocyte count normal karyotype (HL). FAB (French-American-British) Classification system for acute myeloid leukemia is provided for each sample.

Dataset Information

Gene expression analysis of WT and Flt3-ITD multipotent progenitors

Publications

FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors.

Similar Datasets

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