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

ABSTRACT: Juvenile myelomonocytic leukemia (JMML), a clonal hematologic malignancy, originates from mutated hematopoietic stem cells (HSCs) with genetic alterations in the Ras signaling pathway. The mechanism sustaining the persistence of these mutant stem cells leading to leukemia development remains poorly understood. In this study, we conducted comprehensive examination of gene expression profiles, transcriptional factor regulones, and cell compositions throughout various stages of tumor cell development in a mouse model of Ptpn11 mutation-associated JMML. Our analyses unveiled that leukemia-initiating Ptpn11E76K/+ mutant stem cells exhibited de novo activation of the myeloid transcriptional program and aberrant developmental trajectories. Intriguingly, these mutant stem cells displayed significantly elevated expression levels of anti-microbial molecules and pro-inflammatory proteins, particularly S100a9 and S100a8. These proteins conferred a selective advantage to leukemia-initiating cells through autocrine effects and facilitated immune evasion by recruiting and promoting immune suppressive myeloid-derived suppressor cells (MDSCs) to 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 mechanism to establish clonal dominance.

ORGANISM(S): Mus musculus

PROVIDER: GSE266821 | GEO | 2024/09/12

REPOSITORIES: GEO

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