High Risk of Leukemia in Rare Immune Disorder Elucidated

February 25, 2008

Nearly half of patients with severe congenital neutropenia, a rare genetic disorder, possess mutations in the gene encoding granulocyte colony-stimulating factor receptor, and new research elucidates how stem cells bearing this mutation gain clonal advantage over other bone marrow cells, leading to leukemia, according to an article published online Feb. 21 in the Journal of Clinical Investigation.

MONDAY, Feb. 25 (HealthDay News) -- Nearly half of patients with severe congenital neutropenia, a rare genetic disorder, possess mutations in the gene encoding granulocyte colony-stimulating factor (G-CSF) receptor, and new research elucidates how stem cells bearing this mutation gain clonal advantage over other bone marrow cells, leading to leukemia, according to an article published online Feb. 21 in the Journal of Clinical Investigation.

Fulu Liu, M.D., of Washington University School of Medicine in St. Louis, and colleagues used a mouse model to explore the mechanisms by which myeloid cells expressing a mutation in CSF3R, the gene encoding G-CSF, gain clonal dominance over other bone marrow cells.

Knock-in mice expressing a truncated mutant CSF3R gene exhibited a strong clonal advantage among hematopoietic stem cells that depended upon G-CSF levels. G-CSF increased proliferation, phosphorylation and transcription of Stat5 target genes in mice expressing mutant Csf3r. However, this increase was not seen in cells lacking Stat5A or Stat5B, or in mice engineered to have impaired Stat5 activation, suggesting that Stat5 activation plays a key role in the establishment of clonal dominance by mutant stem cells.

"In the present study, we show that expression of a representative G-CSF receptor truncation mutant confers a strong clonal advantage at the hematopoietic stem cell level. However, the clonal dominance is dependent upon exogenous G-CSF administration," the authors conclude.

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