Tumor necrosis factor from leukemic environment stimulates hematopoietic stem/progenitor cells toward...

Area of Science:

• Hematology
• Cancer Biology
• Stem Cell Biology

Background:

• Acute myeloid leukemia (AML) involves malignant myeloid progenitor cell proliferation and hematopoietic system impairment.
• Genetic abnormalities in leukemic cells are known, but damage to the normal hematopoietic system remains poorly understood.
• Mechanisms impairing the residual hematopoietic system in AML bone marrow require further investigation.

Purpose of the Study:

• To investigate the mechanisms underlying the impairment of the residual hematopoietic system in the bone marrow of AML patients.
• To evaluate the function of nonleukemic hematopoietic stem/progenitor cells (HSPCs) in AML bone marrow.
• To determine the role of tumor necrosis factor (TNF) signaling in lineage bias and functional decline of normal HSPCs.

Main Methods:

• Evaluation of residual nonleukemic (nl)-HSPCs from MLL-AF9-induced AML mouse models.
• Analysis of gene expression signatures, including TNF signaling enrichment, in nl-HSPCs.
• Ex vivo expansion of normal hematopoietic stem cells (HSCs)/HSPCs with and without TNF-α.
• Single-cell transcriptome analysis to assess lineage bias and repopulation capacity.

Main Results:

• nl-HSPCs in AML bone marrow exhibited a megakaryocyte (MgK)/myeloid-biased gene expression signature with enriched TNF signaling.
• These nl-HSPCs demonstrated reduced repopulation ability.
• Ex vivo exposure of normal HSCs/HSPCs to TNF-α resulted in increased MgK lineage gene expression and decreased repopulation capacity.

Conclusions:

• Increased TNF-α in the AML bone marrow microenvironment contributes to the differentiation bias of HSPCs toward MgK/myeloid lineages.
• This TNF-α-driven process leads to the exhaustion of residual normal HSCs/HSPCs.
• Findings provide insights into leukemic biology and the disruption of normal hematopoiesis in AML.