Genome wide analysis of SOCS2 dependent gene expression profile in bone marrow LSK following 5-Fluorouracil treatment

ABSTRACT: Hematopoietic stem cells (HSC) promptly adapt hematopoiesis to stress conditions, such as infection and cancer, by replenishing bone marrow (BM)-derived circulating populations while preserving the stem cell reservoir. SOCS2, a feedback inhibitor of JAK/STAT pathways is expressed in most primitive HSC and is upregulated in response to STAT5-inducing cytokines. We demonstrate that Socs2 deficiency unleashes HSC proliferation in vitro sustaining STAT5 phosphorylation in response to the hematopoietic cytokines IL-3, thrombopoietin (TPO) and GM-CSF. In vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-fluorouracil and, in turn, induces exhaustion of long-term HSC function along serial BM transplantations. These findings unveiled a new regulatory role for SOCS2 in normalizing HSC functions under hematopoietic stress and prompted its investigation for involvement in malignant hematopoiesis. Indeed, in acute myeloid and lymphoblastic leukemias high levels of SOCS2 characterize unfavorable subclasses with MLL and BCR/ABL abnormalities. Analysis of gene expression profiles showed that high SOCS2 positively correlates with a pool of genes that are significatively enriched of members of the stemness signature described in acute myeloid leukemia. Unexpectedly, in acute leukemias, SOCS2 and its related genes are not controlled by STAT5 signaling, they are rather part of regulatory networks fronted by IKZF1/Ikaros and MEF2C, two key hematopoietic stemness-related transcriptional factors that, independently, have been described in leukemias but never linked together in controlling SOCS2 expression and unfavorable leukemia outcome.

ORGANISM(S): Mus musculus

PROVIDER: GSE66065 | GEO | 2015/06/01

SECONDARY ACCESSION(S): PRJNA275803

REPOSITORIES: GEO