# Prototypical innate immune mechanism hijacked by leukemia-initiating mutant stem cells for selective advantage and immune evasion in Ptpn11-associated juvenile myelomonocytic leukemia

## TL;DR

Leukemia-causing stem cells in JMML use innate immune signals to gain an advantage and avoid detection by the immune system.

## Contribution

Discovery that S100a9/S100a8 proteins enable immune evasion and selective growth in leukemia-initiating stem cells.

## Key findings

- Leukemia-initiating Ptpn11 mutant stem cells show elevated S100a9/S100a8 expression.
- S100a9/S100a8 signaling promotes immune evasion by recruiting myeloid-derived suppressor cells.
- Pharmacological inhibition of S100a9/S100a8 reduces leukemia development from mutant stem cells.

## Abstract

Juvenile myelomonocytic leukemia (JMML), a clonal hematologic malignancy,
originates from mutated hematopoietic stem cells (HSCs). The mechanism sustaining the
persistence of mutant stem cells, leading to leukemia development, remains elusive. In
this study, we conducted comprehensive examination of gene expression profiles,
transcriptional factor regulons, and cell compositions/interactions throughout various
stages of tumor cell development in Ptpn11 mutation-associated JMML. Our analyses revealed
that leukemia-initiating Ptpn11E76K/+ mutant
stem cells exhibited de novo activation of the myeloid transcriptional
program and aberrant developmental trajectories. These mutant stem cells displayed
significantly elevated expression of innate immunity-associated anti-microbial peptides
and pro-inflammatory proteins, particularly S100a9 and
S100a8. Biological experiments confirmed that S100a9/S100a8 conferred a
selective advantage to the leukemia-initiating cells through autocrine effects and
facilitated immune evasion by recruiting and promoting immune suppressive myeloid-derived
suppressor cells (MDSCs) in the microenvironment. Importantly, pharmacological inhibition
of S100a9/S100a8 signaling effectively impeded leukemia development from
Ptpn11E76K/+ mutant stem cells. These
findings collectively suggest that JMML tumor-initiating cells exploit evolutionarily
conserved innate immune and inflammatory mechanisms to establish clonal dominance.