Senescence and epigenetic reprogramming contribute to SPI1/PU.1-induced-erythroleukemia constituting potential therapeutic targets
Laboratory Molecular dynamic of hematopoietic transformation, Inserm U1170, Gustave Roussy, Villejuif
Thursday, Febuary the 2nd at 9:30 am
Bâtiment Jean Bernard,
Hôpital St-Louis, 16 rue de la Grange aux Belles 75010 PARIS
Hematopoietic cell differentiation depends on the spatiotemporal well-orchestrated action of several transcription factors which altered activities participate to the development of acute myeloid leukemia (AML). Erythroleukemia (AEL) represents a rare but aggressive subtype of AML. Although it is known that alterations in the TP53 suppressor gene are frequent (40%) compared to all AML, biology of AEL remains poorly understood. Interestingly, recent data revealed that >25% of the AELs display an increased expression of key transcriptional regulators that represent a hallmark of the pathology. The SPI1/PU.1 is a major hematopoietic transcription factor overexpressed in AEL that inhibits the erythroid differentiation program. To elucidate how transcription factor deregulation contributes to leukemia initiation and progression, we took advantage of a transgenic mouse model engineered to constitutively express PU.1 and that rapidly (< 4 months) develops erythroleukemia.
We deciphered the partners and mechanistic alterations associated and dependent on the PU.1 aberrant expression that mediate the leukemic transformation.
In particular, I will present how PU.1 unscheduled expression contributes to the replicative stress and senescence bypass that accompany the leukemic development. I will discuss our recent data highlighting the intriguing functional connections between PU.1 and the epigenetic regulators PRC2 and HDAC1, the combined inhibition of which results in synergistic adverse consequences on the leukemic cell survival.
Studying the molecular mechanisms underlying PU.1-induced AEL leads to new hypotheses to be tested in AEL deregulated by other transcriptional regulators, as well as to propose possible targeted therapeutic interventions in this type of high-risk leukemia.
All passed seminars are here.