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Monosomy 7 and activating RAS mutations accompany malignant transformation
in patients with congenital neutropenia
R Kalra, D Dale, M Freedman, MA Bonilla, M Weinblatt, A Ganser, P Bowman, S Abish, J Priest and RS Oseas
Department of Pediatrics, University of California, San Francisco 94143-
0519, USA.
Individuals with severe forms of congenital neutropenia suffer from
recurrent infections. The therapeutic use of recombinant human granulocyte
colony-stimulating factor (rhG-CSF) to increase the neutrophil count is
associated with fewer infections and an improved quality of life. However,
the long-term effects of this new therapy are largely unknown. In
particular, it is unclear if myeloid leukemia, a known complication of some
forms of congenital neutropenia, will occur with increased frequency among
patients who receive long-term treatment with hematopoietic growth factors.
We report 13 patients with congenital disorders of myelopoiesis who
developed leukemic transformation with either myelodysplastic syndrome
(MDS) or acute myelogenous leukemia (AML) and 1 who acquired a clonal
cytogenetic abnormality without evidence of MDS or AML while receiving
rhG-CSF. The bone marrows of 10 patients showed monosomy 7 and 5 had
activating RAS mutations. These abnormalities were not detected in
pretreatment bone marrows and cessation of rhG-CSF was not associated with
either clinical improvement or cytogenetic remission. We conclude that
patients with severe forms of congenital neutropenia are at relatively high
risk of developing MDS and AML. The occurrence of monosomy 7 and RAS
mutations in these cases suggests that the myeloid progenitors of some
patients are genetically predisposed to malignant transformation. The
relationship between therapeutic rhG-CSF and leukemogenesis in patients
with severe chronic neutropenia is unclear.
Volume 86,
Issue 12,
pp. 4579-4586,
12/15/1995
Copyright © 1995 by The American Society of Hematology
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