# Characterization of the clonal hierarchy and immunophenotype of PTPN11 mutations in acute myeloid leukemia

## TL;DR

This study shows that PTPN11 mutations in AML can be early events, leading to diverse myeloid cells and altered immune responses.

## Contribution

PTPN11 mutations are identified as early drivers in AML when paired with strong oncogenic mutations like NPM1.

## Key findings

- PTPN11 mutations can act as initiating events in AML when combined with NPM1 mutations.
- AML with PTPN11 mutations shows a diverse set of variably differentiated myeloid cells.
- A murine model confirmed Ptpn11's role as a codriver with similar immune diversity and engraftment.

## Abstract

Mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) have been considered late acquired mutations in acute myeloid leukemia (AML) development. Using single-cell DNA sequencing, we found that PTPN11 mutations can occur as initiating events in some patients with AML when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The resulting AML has a diverse set of variably differentiated myeloid cells with few myeloid cells that lack leukemic mutations. The role of Ptpn11 as a codriver was confirmed in a murine model that exhibits an AML phenotype with a comparable immune diversity that is serially engraftable and reconstituted from early precursor cells. Furthermore, lineage-negative bone marrow cells from these mice reconstitute the full diversity of mature myeloid cells, and these cells exhibit an altered cytokine response after physiologic stimulation. Our work highlights how PTPN11-mutated AML is derived from a multitude of codominant and late acquired aberrations that have a previously unrecognized differentiated myeloid clonal expansion potentially contributing to pathogenesis of the disease.

PTPN11 mutations in AML can be early events in the clonal evolution of disease development and are associated with variably differentiated myeloid cells.