E-MTAB-1169 - Transcription profiling by array of human acute myeloid leukemia to study ATX expression
Released on 10 May 2013, last updated on 3 May 2014
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.
transcription profiling by array, disease state
Autotaxin is expressed in FLT3-ITD positive acute myeloid leukemia and hematopoietic stem cells and promotes cell migration and proliferation. Claudia Ortlepp, Christine Steudel, Caroline Heiderich, Sina Koch, Angela Jacobi, Martin Ryser, Sebastian Brenner, Martin Bornhäuser, Benedikt Brors, Wolf-Karsten Hofmann, Gerhard Ehninger, Christian Thiede. Exp Hematol 41(5):444-461 (2013), Europe PMC 23377000