Mutations in the Gene for the Granulocyte Colony-Stimulating-Factor Receptor in Patients with Acute Myeloid Leukemia Preceded by Severe Congenital Neutropenia

doi:10.1056/NEJM199508243330804

Volume 333:487-493		August 24, 1995		Number 8

Mutations in the Gene for the Granulocyte Colony-Stimulating–Factor Receptor in Patients with Acute Myeloid Leukemia Preceded by Severe Congenital Neutropenia

Fan Dong, M.D., Ph.D., Russell K. Brynes, M.D., Nicola Tidow, Ph.D., Karl Welte, M.D., Ph.D., Bob Löwenberg, M.D., Ph.D., and Ivo P. Touw, Ph.D.

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ABSTRACT

Background In severe congenital neutropenia the maturation ofmyeloid progenitor cells is arrested. The myelodysplastic syndromeand acute myeloid leukemia develop in some patients with severecongenital neutropenia. Abnormalities in the signal-transductionpathways for granulocyte colony-stimulating factor (G-CSF) mayplay a part in the progression to acute myeloid leukemia.

Methods We isolated genomic DNA and RNA from hematopoietic cellsobtained from two patients with acute myeloid leukemia and historiesof severe congenital neutropenia. The nucleotide sequences encodingthe cytoplasmic domain of the G-CSF receptor were amplifiedby means of the polymerase chain reaction and sequenced. Murinemyeloid 32D.C10 cells were transfected with complementary DNAencoding the wild-type or mutant G-CSF receptors and testedfor their responses to G-CSF.

Results Point mutations in the gene for the G-CSF receptor wereidentified in both patients. The mutations, a substitution ofthymine for cytosine at the codon for glutamine at position718 (Gln718) in one patient and at the codon for glutamine atposition 731 (Gln731) in the other, caused a truncation of theC-terminal cytoplasmic region of the receptor. Both mutant andwild-type genes for the G-CSF receptor were present in leukemiccells from the two patients. In one patient, the mutation wasalso found in the neutropenic stage, before the progressionto acute myeloid leukemia. The 32D.C10 cells expressing mutantreceptors had abnormally high proliferative responses but failedto mature when cultured in G-CSF. The mutant G-CSF receptorsalso interfered with terminal maturation mediated by the wild-typeG-CSF receptor in the 32D.C10 cells that coexpressed the wild-typeand mutant receptors.

Conclusions Mutations in the gene for the G-CSF receptor thatinterrupt signals required for the maturation of myeloid cellsare involved in the pathogenesis of severe congenital neutropeniaand associated with the progression to acute myeloid leukemia.

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From the Department of Hematology, Dr. Daniel den Hoed Cancer Center and Institute of Hematology, Erasmus University, Rotterdam, the Netherlands (F.D., B.L., I.P.T.); the Department of Clinical Pathology, City of Hope National Medical Center, Duarte, Calif. (R.K.B.); and the Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany (N.T., K.W.).

Address reprint requests to Dr. Touw at the Dr. Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, the Netherlands.

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