Blood, 1 April 2001, Vol. 97, No. 7, pp. 2185-2186
CORRESPONDENCE
To the editor:
Significance of neutrophil elastase mutations versus G-CSF
receptor mutations for leukemic progression of congenital neutropenia
Recently, Dale et al1 demonstrated the presence of
a variety of mutations in the gene encoding the serine protease
neutrophil elastase (ELA2) in a high proportion of patients
with congenital neutropenia (CN). Previously, they have reported
mutations in the same gene in patients with autosomal dominant and
sporadic forms of cyclic neutropenia.2 Based on tertiary
structure modeling and on the finding that ELA2 knockout
mice have normal neutrophil levels,3 they propose that
ELA2 mutations alter the structure and biological properties
of neutrophil elastase. This would then lead to accelerated apoptosis
of promyelocytes and their progeny in vivo.
Dale et al discuss their findings in view of previous data showing the
presence of acquired mutations in the G-CSF receptor (G-CSF-R) gene in patients with CN.4-6 These
mutations truncate the carboxy-terminus of the G-CSF-R and
are found in approximately 20% of CN patients. Increasing evidence
suggests that G-CSF-R mutations are associated with leukemic
progression of CN, a major complication observed in about 9% of the
patients.7 Functional studies have indicated that
truncated G-CSF-Rs have altered signaling properties and
give rise to hyperproliferative responses to G-CSF, both in vitro and
in vivo.4,8 In a recent study including 73 CN patients,
G-CSF-R mutations were identified in 16 cases, of which 11 (69%) developed secondary leukemia. In contrast, only 1 of the 57 patients without a G-CSF-R mutation (< 2%) showed leukemic progression.9
Dale et al now consider it more likely that ELA2 mutations,
rather than G-CSF-R mutations, contribute to leukemic
progression of CN. They state that "current prevalence data suggest
that a minority of [the CN] patients manifest [G-CSF receptor
mutations], and it now seems much more likely that mutations of the
gene for neutrophil elastase lead to compromised myeloid
differentiation and create the risk for development of
AML."1(p2321) We feel that this statement is not
supported by the data presented in their paper nor by other data
generated to date. First, the frequencies of leukemic progression
14%
(3 of 21) in the group with, versus 25% (1 of 4) in the group without,
ELA2 mutationsdo not point toward a correlation between
mutated neutrophil elastase and leukemic transformation. Second,
despite the high incidence of ELA2 mutations in cyclic
neutropenia, 2 of which (16073G>A and 15862C>T) are also found
in CN, none of the 132 cyclic neutropenia patients reported so far
developed leukemia. How the ELA2 mutations contribute to the
pathogenesis of neutropenia remains unclear until the biological
properties of the various mutated neutrophil elastase proteins have
been elucidated. But there is no indication that ELA2
mutations are involved in leukemic progression of CN.
Mirjam H. A. Hermans and Ivo P. Touw
Institute of Hematology Erasmus University Rotterdam
Rotterdam, Netherlands
References
1.
Dale DC, Person RE, Bolyard AA, et al.
Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.
Blood.
2000;96:2317-2322[Abstract/Free Full Text].
2.
Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC.
Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.
Nat Genet.
1999;23:433-436[CrossRef][Medline]
[Order article via Infotrieve].
3.
Belaaouaj A, McCarthy R, Baumann M, et al.
Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis.
Nat Med.
1998;4:615-618[CrossRef][Medline]
[Order article via Infotrieve].
4.
Dong F, Brynes RK, Tidow N, Welte K, Lowenberg B, Touw IP.
Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.
N Engl J Med.
1995;333:487-493[Abstract/Free Full Text].
5.
Tidow N, Pilz C, Teichmann B, et al.
Clinical relevance of point mutations in the cytoplasmic domain of the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia.
Blood.
1997;89:2369-2375[Abstract/Free Full Text].
6.
Tidow N, Pilz C, Kasper B, Welte K.
Frequency of point mutations in the gene for the G-CSF receptor in patients with chronic neutropenia undergoing G-CSF therapy.
Stem Cells.
1997;15(suppl 1):113-119.
7.
Freedman MH, Bonilla MA, Fier C, et al.
Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.
Blood.
2000;96:429-436[Abstract/Free Full Text].
8.
Hermans MH, Antonissen C, Ward AC, Mayen AE, Ploemacher RE, Touw IP.
Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene.
J Exp Med.
1999;189:683-692[Abstract/Free Full Text].
9.
Germeshausen M, Tidow N, Pilz C, Tschan C, Zeidler C, Welte K.
G-CSF receptor mutations in patients with severe congenital neutropenia: frequency and implications in leukemic development [abstract].
Blood.
1999;94:45a.
Response:
Neutrophil elastase and congenital neutropenia
Drs Hermans and Touw have questioned the suggestion in our paper
that mutations of the gene for neutrophil elastase create the risk for
leukemia in patients with congenital neutropenia. We made this
hypothesis based on the following:
1. Most patients with severe congenital neutropenia have mutations of
the gene for neutrophil elastase (ELA2). At the recent meeting of the American Society of Hematology, we updated the information in our paper and reported that 45 of 49 patients examined have mutations of the ELA2 gene. Thus this mutation is far
more common than mutations of the G-CSF receptor gene
(G-CSF-R).1
2. Our report indicates that families with autosomal dominant
congenital neutropenia have the same mutation in all family members.
This demonstrates that these are germline mutations and not acquired
mutations. Thus far, all evidence points to the G-CSF-R mutations as being acquired mutations.2
3. We have now serially studied one patient with congenital
neutropenia, having a mutation of the ELA-2 gene, who then
developed leukemia. Prior to the development of leukemia, the
G-CSF-R was normal, but the ELA-2 gene was
abnormal. The G-CSF-R became abnormal when he developed
leukemia.3
4. In our Seattle studies of patients with severe congenital
neutropenia evolving to leukemia, 6 of 7 patients have had ELA2 mutations. Five of the 6 with ELA2 gene mutations
evolving to leukemia have had G-CSF-R mutations.
5. In cellular studies, we have found that patients with congenital
neutropenia and mutations of the ELA2 gene have accelerated apoptosis of CD34+ precursor cells. In patients evolving to
leukemia and having G-CSF-R mutations, we have found that
the cells manifest longer survival. It may be inferred that cells
bearing the mutant receptor accumulate as part of the leukemic transformation.
Based on these data, we agree with Drs Hermans and Touw that
G-CSF-R mutations are common in patients with congenital
neutropenia who develop leukemia. Thus far, the data is compelling in
indicating that the mutations in the gene for ELA2 come first.
David C. Dale and Andrew Aprikyan
Department of Medicine University of Washington Seattle,
Washington
References
1.
Aprikyan AG, Germeshausen M, Redger ER, et al.
The diversity of neutrophil elastase mutations in congenital neutropenia [abstract].
Blood
2000;96:445a.
2.
Dale DC, Person RE, Bolyard AA, et al.
Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.
Blood.
2000;96:2317-2322.
3.
Aprikyan AG, Redger ER, Jeha S, et al.
Acquired substitution mutation in G-CSF receptor underlying evolution of severe congenital neutropenia to acute myelogenous leukemia [abstract].
Blood.
2000;96:185b.
