Novel agents targeting pathways downstream of the JAK/STAT signaling pathway in MF. Activated JAK2 signals through and activates downstream signaling intermediates such as STAT5, RAS/MAPK, and PI3K/AKT/mTOR pathways, leading to effects on proliferation and survival of MPN cells. JAK proteins can be down-modulated by the use of HSP90 inhibitors or HDAC inhibitors, which lead to targeting of both wild-type and mutant proteins for degradation by the proteosomal system. PI3K/AKT inhibitors, mTOR inhibitors, MEK inhibitors, and STAT inhibitors can inhibit the respective signaling intermediates downstream of JAK/STAT pathway. DNMT inhibitors can potentially reverse epigenetic silencing of various genes including the SOCS genes, which are negative regulators of the JAK/STAT signaling pathway.