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Blood, 15 January 2005, Vol. 105, No. 2, pp. 584-591.
Prepublished online as a Blood First Edition Paper on September 7, 2004; DOI 10.1182/blood-2004-07-2613.
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Submitted July 14, 2004
Accepted August 23, 2004
Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia
Lawrence J Druhan, Jing Ai, Pam Massullo, Tamila Kindwall-Keller, Mark A Ranalli, and Belinda R Avalos*
The Bone Marrow Transplant Program, The Ohio State University, Columbus, OH, USA; Division of Hematology/Oncology, The Ohio State University, Columbus, OH, USA
The Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH, USA
Division of Hematology/Oncology, The Ohio State University, Columbus, OH, USA
Department of Hematology/Oncology, Children's Hospital, Columbus, OH, USA
The Bone Marrow Transplant Program, The Ohio State University, Columbus, OH, USA; Division of Hematology/Oncology, The Ohio State University, Columbus, OH, USA; The Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH, USA
* Corresponding author; email: avalos-1{at}medctr.osu.edu.
Severe congenital neutropenia (SCN) is a rare disease diagnosed at or soon after birth characterized by a myeloid maturation arrest in the bone marrow, ineffective neutrophil production, and recurrent infections. Most patients respond to treatment with G-CSF and the majority harbor mutations in the neutrophil elastase gene. In the subset of patients with SCN transforming to AML, mutations that truncate the cytoplasmic tail of the G-CSFR have been detected. Here we report a novel mutation in the extracellular portion of the G-CSFR within the WSXWS motif in a patient with SCN without AML who was refractory to G-CSF treatment. The mutation affected a single allele and introduced a premature stop codon that deletes the distal extracellular region and the entire transmembrane and cytoplasmic portions of the G-CSFR. Expression of the mutant receptor in either myeloid or lymphoid cells was shown to alter subcellular trafficking of the wild-type (WT) G-CSFR by constitutively heterodimerizing with it. WT/mutant G-CSFR heterodimers appeared to be retained in the endoplasmic reticulum and/or Golgi and accumulate intracellularly. These findings together with two previous case reports of extracellular mutations in the G-CSFR in patients with SCN unresponsive to G-CSF suggest a common mechanism underlying G-CSF refractoriness.
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