Activating RAS mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and were found in some patients with severe congenital neutropenia (CN) after transformation to MDS/AML (

Kalra et al.
Blood
1995
;
86
:
4579
). CN is a rare genetic disorder characterized by severe neutropenia leading to recurrent life-threatening bacterial infections due to the failure of myeloid cells to mature from promyelocytes and myelocytes to neutrophils. The risk for malignant transformation in CN is currently estimated at 14%. Based on earlier investigations one proposed model of the genetic events associated with progression of CN to MDS/leukemia starts with the acquirement of a somatic G-CSF Receptor gene (G-CSFR) mutation. In this model, RAS mutations and chromosomal aberrations such as monosomy 7 or trisomies represent late events in the transformation process. We have screened bone marrow specimens from 44 CN patients for mutations in the G-CSFR and in the KRAS2 and NRAS genes. Remarkably, we not only identified G-CSFR mutations in 10 out of 14 CN patients with MDS/AML, but also in 21 out of 30 patients without transformation. Only 1 out of 44 patients with CN harbored an activating RAS mutation (NRAS, c.37G>C; G13R). In this patient, who developed secondary chronic myelomonocytic leukemia at the age of 18, the NRAS mutation was not detected in a bone marrow sample obtained at age 2. Results of cytogenetic investigations were available for 10 out of the 14 CN/MDS/leukemia patients. Chromosomal abnormalities were detected in all 10 patients, and included monosomy 7 (n=3), trisomies (n=3), deletions (n=2) and translocations (n=5). In addition to the cohort of 44 patients mentioned above, we analyzed 3 of the 5 CN patients with secondary myeloid leukemia in whom a NRAS mutation, c.35G>A (G12D), was described previously (
Kalra et al.
Blood
1995
;
86
:
4579
). None of these patients carried a G-CSFR mutation. Combining our data with data available from the literature the frequency of RAS mutations in CN patients is now 6/55 (11%). Accordingly, RAS mutations are less common during leukemic progression in CN than suggested by earlier studies, which may reflect changes in demographics of the CN population and/or effects of early treatment with G-CSF. The sequential occurrence of G-CSFR and RAS mutations in the leukemogenesis is very rare. Instead, our genetic data suggest RAS and the G-CSFR mutations are largely mutually exclusive in CN and may deregulate common signaling pathways.

Topics:
congenital neutropenia, granulocyte colony-stimulating factor receptors, leukemogenesis, mutation, receptors, colony-stimulating factor, bone marrow specimen, leukemia, bacterial infections, genetic disorder, granulocyte colony-stimulating factor

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2005, The American Society of Hematology
2005
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