Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of 
progression to acute myeloid leukemia (AML). The underlying genetic changes 
involved in SCN evolution to AML are largely unknown. We obtained serial 
hematopoietic samples from an SCN patient who developed AML 17 years after the 
initiation of G-CSF treatment. Next- generation sequencing was performed to 
identify mutations during disease progression. In the AML phase, we found 12 
acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, 
co-occurred in a subpopulation of progenitor cells already in the early SCN 
phase. This population expanded over time, whereas clones harboring only CSF3R 
mutations disappeared from the BM. The other 9 mutations were only apparent in 
the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and 
chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that 
conferred autonomous proliferation to myeloid progenitors was found. We conclude 
that progression from SCN to AML is a multistep process, with distinct mutations 
arising early during the SCN phase and others later in AML development. The 
sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a 
driver of leukemic transformation in this case of SCN.