The Prenatal And Postnatal Bone Marrow Niche Origin Of Leukemia

Human leukemia is a multistep and evolutionary process.At present,based on large amount of gene expression prifiles analysis of patient samples,the classification of leukemia and biological study become effective.Some researchers even have reported the specific gene expression patterns on the leukemic stem cells(LSCs).All of these gene expression patterns among different cell population are based on the cell surface markers(the immune molecules on the surface of cell)and their immue properties.Undeniably,defining or identifing leukemia cell phenotype through immune molecules on the cell surface does not reflect the origin of leukemia.Studying the origin of leukemia makes senses in the early clinical diagnosis of malignant leukemia and preventing leukemia.It also can provide preventive treatment for leukemia for a high-risk human population.This research mainly studied the prenatal and postnatal bone marrow niche origin of leukemia.1.Prenatal originResearchers speculate that tumor cells with embryonic cell characteristics may originated from prenatal cells.It has been reported that most of the chromosome translocation related leukemia originated from prenatal cells.Subsequent studies have proved that a large number of children or adolescents malignant leukemia originated from prenatal cells.Fev(also known as petl)is a member of the ETS transcription family.Our collaborators find that Fev is expressed in the zebrafish embryo and play an important role in the generation of hematopoietic stem cells.Thus we have our hypothesis:Fev gene plays a very important role in the hematopoiesis system of higher mammal Firstly,we detected the expression pattern of Fev in different development stages of human hematopoietic stem/progenitor cells by using reverse-transcription PCR.We found that the Fev is only expressed in prenatal hematopoietic stem/progenitor cells and can not be detected in newborn and adult bone marrow hematopoietic system Then we detected the Fev expression in murine hematopoietic cells before and after the birth and the results are consist with that of human.So we get the conclusion that Fev is expressed in prenatal hematopoietic stem cells and silenced in postnatal hematopoietic stem cells.Our previous study shows that Fev regulates self-renewal ability of hematopoietic stem cells and leukemia stem cells.It is interesting to note that some acute myeloid leukemia(AML)and acute lymphoid leukemia(ALL)patient samples re-express FevThis kind of expression profile suggests that Fev can serve as a marker gene to study the origin of prenatal and postnatal leukemia.In order to further study whether the re-expressed Fev in leukemic cells is retained from prenatal hematopoietic stem cells or reactivated from hematopoietic stem cells during leukemia pathogenesis.We over-expressed MLL-AF9 or N-myc leukemic genes respectively in prenatal and postnatal hematopoietic stem/progenitor cells.Then we detected Fev expression in leukemic cells from different cell origin.Our results prove that the re-expressed Fev in leukemic cells is retained from fetal liver hematopoietic stem cellsTo sum up,our research reports that Fev is closely related to clinical prognosis and can distinguish normal adult hematopoietic stem cells and leukemia stem cells.Our result sugests that Fev probably can be used as a clinical judgment index of prenatal origin of leukemia.2.2.Postnatal bone marrow niche originTEL-AML1 fusion gene is very common in childhood leukemia.Genetic study result shows that about 25%of children with acute lymphoid leukemia(ALL)is t(12,21)chromosome translocation.In order to study the bone marrow microenvironment origin of leukemia,we have generated the TEL-AML1 mouse model.By immunohistochemical,we found that TEL-AML1 positive cells distribute in endosteal niche specificly,but the control group GFP+scatteredly distributed in the marrow cavity.This suggests Fev play an important role in the process of leukemia development.