The most predominant molecular theory is the so-called “two-hit” model of MDS progression to AML in which sequential genetic alterations in genes altering cellular differentiation (e.g., TET2 or RUNX1) followed by a second “hit” in a gene impacting cellular proliferation and survival (e.g., FLT3, NPM1, IDH1) eventually result in leukemic transformation from antecedent MDS [16,17]. Here, NPM1 is linked to myelodysplastic syndrome.