PBX1-directed stem cell transcriptional program drives tumor progression in myeloproliferative neoplasm

ABSTRACT: Summary PBX1 regulates the balance between self-renewal and differentiation of hematopoietic stem cells and maintains proto-oncogenic transcriptional pathways in early progenitors. Its increased expression was found in myeloproliferative neoplasm (MPN) patients bearing the JAK2V617F mutation. To investigate if PBX1 contributes to MPN, and to explore its potential as therapeutic target, we generated the JP mouse strain, in which the human JAK2 mutation is induced in the absence of PBX1. Typical MPN features, such as thrombocythemia and granulocytosis, did not develop without PBX1, while erythrocytosis, initially displayed by JP mice, gradually resolved over time; splenic myeloid metaplasia and in vitro cytokine independent growth were absent upon PBX1 inactivation. The aberrant transcriptome in stem/progenitor cells from the MPN model was reverted by the absence of PBX1, demonstrating that PBX1 controls part of the molecular pathways deregulated by the JAK2V617F mutation. Modulation of the PBX1-driven transcriptional program might represent a novel therapeutic approach. Graphical abstract Highlights • In the novel JP mouse, the JAK2V617F MPN-driver mutation is induced without Pbx1• In JP mice, typical MPN features did not develop or resolved over time• The stem cell gene Pbx1 is a key contributor in establishing and maintaining MPN• Pbx1-dependent pathways may represent novel therapeutic targets for MPN Ficara and colleagues generated a mouse model in which the human JAK2V617F myeloproliferative neoplasm (MPN) driver mutation is induced in the absence of the transcription factor Pbx1. Typical disease features did not develop or resolved over time, demonstrating that Pbx1 is a key contributor in establishing and maintaining MPN. Pbx1-dependent genes and pathways may represent novel therapeutic targets.

SUBMITTER: Muggeo S 

PROVIDER: S-EPMC8581051 | biostudies-literature |

REPOSITORIES: biostudies-literature