github link
Accession IconGSE53352

Hematopoietic stem cells progressively deficient of glycogen synthase kinase initiate a pre-neoplastic state required for evolution to acute leukemia

Organism Icon Mus musculus
Sample Icon 10 Downloadable Samples
Technology Badge Icon Affymetrix Mouse Genome 430 2.0 Array (mouse4302)

Submitter Supplied Information

Description
The cellular origin and molecular progression towards aggressive cancers such as acute myeloid leukemia (AML) remain elusive. Clinically, Myelodysplastic syndromes (MDS) and related myeloproliferative neoplasias (MPN) disorders1-5 are believed to present as a precursor stage to lethal AML development. Despite the identification of cytogenetic abnormalities and increased activation of signaling in human MDS/MPN, specific pathways that either sustain or initiate disease progression and evolve into self-sustaining leukemic-initiating cells (L-ICs)13 have not been elucidated. Here we demonstrate that tissue specific loss of glycogen synthase kinase-3 (GSK3 beta) initiates the emergence of stable Pre-leukemic-ICs (PLIC) in vivo. In contrast to deletion or transgenic perturbation of pathways associated with AML eg. -catenin/Wnt, serial transplantation of PL-IC produced abnormal hematological disease that phenotypically and molecularly resembles human MDS/MPN. PL-ICs were exclusively generated from GSK3 beta deficient hematopoietic stem cells (HSCs), indicating that disease initiation events collaborate with existing HSC self-renewal machinery. In the absence of GSK3 beta, subsequent deletion of GSK3 beta caused rapid induction of L-ICs that give rise to lethal AML. As these processes were solely driven by dose-dependent deficiencies in GSK3 beta levels, our results suggest that perturbation of this pathway can sufficiently drive and recapitulate a step-wise progression of disease from HSCs to MDS/MPN and subsequent AML. Our study provides a molecular and cellular foundation to understand AML evolution from pre-leukemic precursors. We suggest that defining the molecular states of pre-neoplastic disease will allow patient stratification at early stages of MDS/MPN onset and aid in the development of therapeutic targeting of causal pathways responsible for the earliest stages of leukemic initiation events.
PubMed ID
Total Samples
10
Submitter’s Institution

Samples

Show of 0 Total Samples
Filter
Add/Remove
Accession Code
Title
Sex
Specimen part
Processing Information
Additional Metadata
No rows found
Loading...