A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML

Area of Science:

• Hematology
• Oncology
• Stem Cell Biology

Background:

• Cancer initiation involves complex interactions between tumor cells and their microenvironment.
• Tumor-promoting inflammation is a key factor in tumorigenesis, but its precise mechanisms are not fully understood.
• Understanding intercellular signaling in the bone marrow niche is crucial for deciphering leukemia development.

Purpose of the Study:

• To decipher predicted intercellular signaling between hematopoietic stem/progenitor cells (HSPCs) and their neoplastic counterparts in the human bone marrow niche.
• To identify regulatory roles of stromal cells and the impact of inflammatory niche remodeling in NPM1-mutated acute myeloid leukemia (AML).
• To explore the association between stromal gene signatures, niche remodeling, and clinical outcomes in AML patients.

Main Methods:

• Adapted single-cell RNA sequencing was employed to predict intercellular signaling networks.
• Analysis focused on interactions within the native bone marrow niches of human AML patients.
• Stromal gene signatures were correlated with clinical data, including relapse rates and treatment outcomes.

Main Results:

• LEPR+ stromal cells were identified as central regulators of hematopoiesis through predicted interactions.
• Inflammatory niche remodeling was predicted to repress critical regulatory factors for HSPCs in AML, favoring clonal cell survival.
• Stromal gene signatures indicative of niche remodeling correlated with reduced relapse rates and favorable outcomes post-chemotherapy.

Conclusions:

• Inflammatory remodeling of stem cell niches drives tissue repression and clonal selection in human AML.
• This inflammatory process may create a vulnerability in relapse-initiating cells, exploitable by chemotherapeutic treatment.
• Deciphering intercellular communication in the AML niche provides insights into disease progression and therapeutic strategies.