2017 – RELEVANCE OF DORMANT CANCER STEM CELLS IN DISEASE PROPAGATION AND THERAPY RESISTANCE IN JAK2V617F-DRIVEN MPN

• Published in: Experimental hematology Vol. 137; p. 104574
• Main Authors: Ghezzi, Ian, Öz, Sercan, Erdogru, Selin, Correa, Esther Rodríguez, Fotopoulou, Foteini, Alptekin, Sena, Bognar, Lena, Milsom, Michael
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2024
• ISSN: 0301-472X
• DOI: 10.1016/j.exphem.2024.104574

Long-term dormancy is proposed to mediate therapy resistance of cancer stem cells. However, the biological relevance of dormancy in hematologic malignancies has not been formally addressed. Using a novel mouse model that allows identification and isolation of dormant label retaining cells (LRCs) in the setting of JAK2V617F-driven Polycythemia Vera (PV), we could identify LRCs that maintained dormancy for at least 20 weeks in vivo in PV mice, despite harboring the pro-proliferative JAK2 mutation. Isolation and transplantation of mutant LRCs and nonLRCs unambiguously demonstrated that only LRCs were capable of propagating the PV phenotype. Treatment of primary PV mice with a JAK2 inhibitor (Fedratinib, FED) failed to target mutant LRCs, while pegylated interferon-a (IFNa) reduced their number, in line with the clinical observation that IFNa can facilitate molecular remission while FED cannot. After therapy, purified residual LRCs were still uniquely able to propagate PV, demonstrating their role as disease-reinitiating cells and that their level of depletion is a biomarker of PV eradication. Side effects of IFNa treatment limit its clinical effectiveness in PV. To circumvent this, we explored using low dose IFNa (IFNaLD) alone or in concert with FED. IFNaLD alone had no impact on mutant LRC numbers, while IFNaLD plus FED resulted in a synergistic depletion of mutant LRCS and correction of PV phenotype, suggesting that IFNaLD renders LRCs dependent upon JAK2 signaling. In summary, we provide definitive evidence of the importance of dormancy in propagation and therapy resistance of PV; create a model for pre-clinical evaluation of novel therapies for PV; and demonstrate that a combination of IFNaLD and FED may be effective at eliminating mutant LRCs while limiting side effects of standard IFNa treatment.