Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.
Bottom Line: The best JAK2/JAK1 and PI3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK2 V617F.It also exerted strong inhibitory effects on erythropoietin-independent erythroid colonies from MPN patients and JAK2 V617F knock-in mice, where at certain doses, a preferential inhibition of JAK2 V617F mutated progenitors was detected.Our data support the use of a combination of JAK2 and pan-class I PI3K inhibitors in the treatment of MPNs.
Affiliation: Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore.Show MeSH
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Mentions: Female BALB/c nude mice injected with Ba/F3 TpoR JAK2 V617F cells were studied for overall survival and enlargement of spleen (Fig. 5). Tissue samples were collected from mice killed on day 8 and day 14. Spleen weight increased after 8 days of cell implantation, while increase of liver weight was observed by day 14 (Fig. S5A). A progressive increase of Ba/F3 TpoR JAK2 V617F cells in the systemic blood circulation and spleen was observed from day 8 to day 14 (Fig. S5B). An increase of Ba/F3 TpoR JAK2 V617F cells in the bone marrow was observed on day 8 (results not shown). Platelet and red blood cell numbers decreased when compared with the control groups, most likely because of replacement by proliferating Ba/F3 transformed cells (Fig. S5C).
Affiliation: Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore.