An important question is whether the mutations occur in a necessary order or randomly until differentiation of the malignant hematopoietic clone is completely blocked. RARS HD-0173 (one
RUNX1 mutation) and AML HD-0790 (two
RUNX1 mutations) are instructive samples from the same patient. It is tempting to interpret this observation as a bi-allelic inactivation of the
RUNX1 gene.
RUNX1 mutations are frequent in chronic myelomonocytic leukemia [
19] but rare in myeloproliferative neoplasms except at the acute phase [
35]. In our series, mutations in
TET2 were equally frequent in MDSs and AMLs. Taken together this suggests that inactivation of class I tumor suppressors (
RUNX1, TET2) can intervene at any stage, i.e. early or at progression. In studies of AMLs secondary to myeloproliferative neoplasms (MPN) mutations of
TET2 have indeed been shown to occur early or late [
30,
36]. A recent study showed that
ASXL1 mutations were present at the chronic stage and, in agreement with our findings, that
ASXL1,
JAK2 and
TET2 have non overlapping contributions to myeloid transformation [
36]. The order of occurrence of
ASXL1,
TET2 and
RUNX1 mutations may vary in different diseases (MPNs and MDSs) and in different patients. However, the number of paired cases was much too low in our series to draw any firm conclusion. The study of more paired cases is necessary to definitely clear this issue. In contrast, some mutations such as
IDH1 and
IDH2 amino acid changes were detected at the AML rather than the MDS stage. Mutations in proliferation genes - except in
CBL - were rare in MDS. Taken together this suggests that mutations in classes III and IV may occur late in leukemogenesis.