<i>PTPN11</i> Mutation Clonal Hierarchy in Acute Myeloid Leukemia

Mutations in protein tyrosine phosphatase non-receptor type 11 ( <i>PTPN11</i> ) have been considered late acquired mutations in acute myeloid leukemia (AML) development. To interrogate the ontogeny of <i>PTPN11</i> mutations, we utilized single-cell DNA sequencing and identified that <i>PTPN11</i> mutations can occur as initiating events in some AML patients when accompanied by strong oncogenic drivers, commonly <i>NPM1</i> mutations. The co-driver role of <i>PTPN11</i> mutations was confirmed in a novel murine model that exhibits an AML phenotype with early expansion of a diverse set of variably differentiated myeloid cells that engrafted into immunodeficient and immunocompetent mice. This immune diversity was reconstituted from early precursor cells when engrafted into immunodeficient mice. Moreover, immune diversity was also observed in the blast component of patient samples with <i>NPM1</i> and <i>PTPN11</i> mutations, providing novel antigen targets for immune based approaches in this subset of AML that is resistant to multiple targeted therapies.