IFN-I-Mediated Transcriptional Reprogramming Drives Myeloid-skewed Hematopoiesis in Sickle Cell Anemia

TL;DR

This study reveals that type I interferon signaling causes abnormal myeloid cell production in sickle cell anemia, contributing to chronic inflammation.

Contribution

The study identifies IFN-I-mediated transcriptional reprogramming as a novel driver of myeloid-skewed hematopoiesis in sickle cell anemia.

Findings

Hematopoietic stem cells in SCA show transcriptional reprogramming toward myeloid differentiation.

IFN-I signaling promotes premature myeloid commitment and monocytic skewing via CSF3R upregulation.

Hydroxyurea reduces IFN-I signaling, aligning with its anti-inflammatory effects in SCA.

Abstract

Neutrophils and monocytes are persistently elevated in sickle cell anemia (SCA), yet the intrinsic mechanisms driving pathological myelopoiesis and inflammation remain poorly defined. Through single-cell RNA sequencing and functional assays, we demonstrate that hematopoietic stem and multipotent progenitor cells (HSPCs) in SCA are transcriptionally reprogrammed toward myeloid differentiation. This process is orchestrated by aberrant activation of type I interferon (IFN-I) signaling, which promotes premature myeloid commitment of hematopoietic stem cells. SCA progenitors further exhibit unexpected responsiveness to granulocyte colony-stimulating factor (G-CSF) through upregulation of CSF3R, resulting in skewed myelopoiesis toward the monocytic lineage. Importantly, hydroxyurea treatment attenuates IFN-I signaling in neutrophils, consistent with its therapeutic role in reducing excessive inflammation and granulopoiesis. Collectively, these findings uncover IFN-I–driven remodeling of hematopoiesis as a fundamental mechanism of leukocytosis and chronic inflammation in SCA, and establish a tractable therapeutic axis to mitigate innate immunity activation in this disease.

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