Progression to Dnmt3aR878H/+Npm1cA/+ AML was also associated with these same mutations, but with the addition of mutations activating the tyrosine phosphatase SHP2 (Ptpn11), PI3K (Pik3r1), or Flt3 (Flt3) signaling as well as mutations involved in epigenetic regulation including Brd4, Hdac1, Idh1, and Arid1a. Many of these genes are recurrently mutated in human AML [35–37], and demonstrate additional mutations are required to cooperate with mutant Dnmt3a and Npm1 to promote transformation to MDS/MPD, MPD and AML. This evidence concerns the gene NPM1 and acute myeloid leukemia.