In leukemia’s most aggressive settings, bone marrow–resident blood-cell factories fail to complete normal maturation. Instead of rapidly generating mature immune cells, immature progenitors stall, expanding without performing their intended functions. Over time, this interruption contributes to the accumulation of dysfunctional cells and the collapse of healthy blood production.
Raquel Espin Palazon and colleagues at Iowa State University investigated why this differentiation breakdown occurs. Their work centers on progranulin, a widely expressed protein known for roles in cell growth, tissue repair, and inflammation, but whose myeloid-specific function was unclear.
The team leveraged a challenge: in mammals, progranulin is produced from a single gene throughout many tissues, making it difficult to isolate effects on blood-cell development. To overcome this, they used zebrafish, which contain two progranulin genes, enabling more precise, blood-related perturbations.
Earlier zebrafish work from the same group indicated that one blood-expressed progranulin gene is required for myeloid progenitors to mature into macrophages and neutrophils. Building on that foundation, the researchers attempted to stimulate human leukemia cells with progranulin to see whether differentiation could be rescued, initially without success.
They then returned to zebrafish lacking the blood-cell progranulin component and mapped the downstream consequences. A key defect emerged in the JAK2/STAT3 signaling axis, a pathway that transduces extracellular cues to nuclear gene-expression programs.
Crucially, both progranulin and active JAK2/STAT3 were required for definitive myeloid fate decisions. In leukemia contexts where JAK2/STAT3 signaling is hyperactivated, adding progranulin restored maturation capacity, pushing cells to complete a differentiation trajectory that culminates in their loss through normal lifecycle progression.
Beyond leukemia, the study distinguishes embryonic macrophage populations with different molecular dependencies. One population depends on both progranulin and JAK2/STAT3, while another does not, suggesting that macrophage “identity” is partially encoded by signaling logic during development.
The findings point to a therapeutic strategy: combine pathway activation states with targeted differentiation cues rather than relying solely on cytotoxic approaches. If translated, interventions that modulate progranulin-dependent signaling could steer malignant progenitors toward terminal maturation.
Researchers caution that clinical development will take years, including validation of safety, delivery, and whether pathway states in patients predict responsiveness. Still, the work demonstrates how in vivo models can reveal synergistic requirements that isolated cell systems can miss.
Subject of Research: Myeloid leukemia
Article Title: Synergistic cooperation between progranulin and Jak2/Stat3 signaling determines definitive myeloid cell fate
News Publication Date: 10-Jun-2026
Web References: http://dx.doi.org/10.1016/j.celrep.2026.117477
References: Cell Reports (10.1016/j.celrep.2026.117477)
Image Credits: Raquel Espin Palazon/Iowa State University
Keywords: leukemia; myeloid differentiation; progranulin; JAK2/STAT3; zebrafish; macrophages; signaling synergy; immune cell fate
Tags: blood cell differentiationblood cell maturation disruptioncancer therapy targeting blood cell pathwaysdysfunction in blood cell productionimmune cell development in leukemiaimmune cell differentiationJAK2/STAT3 signaling pathwayleukemia therapy developmentmyeloid progenitor maturationprogranulin function in hematopoiesisrole of progranulin in inflammationzebrafish models of blood development
