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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 726-728
CORRESPONDENCE
 |
Letter |
To the editor:
C-kit mutations in core binding factor leukemias
Positivity for CD117(c-kit) expression is present in
80% of acute myeloblastic leukemia (AML)
cases,1 and has been associated with the expression of
CD33, a marker of myeloid precursors, and CD13, a myeloid-associated
antigen.2 Combined positivity for the stem cell antigens
CD34, CD117, and HLA-DR characterizes AML-M2 with t(8;21) and AML-M4Eo
with inv(16), currently designated core binding factor (CBF)
leukemias.3-5 According to a recent study, the
PEBP2 /MYH11 fusion transcript is involved in
CD34+/c-kit+ immature cells and
may have leukemogenic potential only in these cells.6 The
same authors pointed out that the disruption of AML1 and PEBP2 genes
encoding the  and subunits of a single transcriptional complex
(CBF) affects the same differentiation stage of the myeloid cells. On
the basis of published data concerning c-kit (CD117) expression in CBF
leukemias,6-8 and our finding of the Asp816Tyr activating
c-kit mutation in an AML-M2 patient with t(8;21),9 we
recruited 15 patients with either AML-M2 with t(8;21) or AML-M4Eo with
inv(16) to screen for c-kit mutations. Mutation screening was targeted
on exon 17 as codon 816 was found to be affected by Asp816Val first
detected in the mast cell leukemia cell line HMC-110 and
the alternative mutation Asp816Tyr.9 As can be seen in the
Table, c-kit mutations at the critical
codon 816 were found in 4 AML-M2 and 2 AML-M4Eo patients. Only patient 1 was found to carry the Asp816Tyr mutation which, as previously reported, was present in 100% of blasts.9 The application
of DGGE/CDGE to screen for the presence of the Asp816Tyr mutation did
not reveal any other carrier among the patients recruited for this
study. The presence of the Asp816Val mutation, which creates
an additional HinfI site, leads to a new DNA fragment that is detected
by HinfI digestion of c-kit exon 17 PCR products. As a result of HinfI
digestion of the mutated allele, the 147 bp DNA fragment
was apparent in AML patients 2, 5, 8, 13 and 15 (Figure
1). The molecular test at remission in
patients 5 and 15 is also shown. There was a remarkable variability in
the intensity of the 147 bp band due to the different expansion of the
mutated leukemic clone among the patients. During follow-up monitoring using the same HinfI assay in patients 5 and 15, the mutated allele in
purged bone marrow DNA at remission was undetectable
(lanes 5a and 15a), indicating a contraction of the mutant clone
together with disease. The targeted selection of AML patients
with antigenic and karyotypic features of CBF leukemias thus allowed us
to identify 6 out of 15 patients carrying either a D816V or a
D816Y c-kit mutation. These results confirm the strict correlation
between the stage of myelomonoblast differentiation and the
susceptibility to c-kit activation. Our previous analysis of 12 unselected AML patients did not lead to the detection of any c-kit
mutation, which is in line with the results of the study reported by
Ferrao,11 who found that only one AML-M2 patient out of 33 AML cases carried the D816V mutation. Mutation screening of all 21 c-kit exons has recently disclosed new c-kit mutations in
AML,12 which underlines their relevance in CBF leukemias.
View larger version (59K):
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| Fig 1.
HinfI assay for detection of Asp816Val c-kit mutation.
Digestion of the 212 bp exon 17 polymerase chain reaction
(PCR) product gives rise to a 161 bp DNA fragment r: when an
A-T transition is present, an additional HinfI site is created
leading to a 147 bp DNA fragment. This additional fragment was
present in patients 2, 5, 8, 13 and 15 as well as in a patient with
systemic mastocytosis included as positive control (lane C+). The
negative controls were undigested (lane C0) and
digested (lane C ) DNAs from normal subjects. Molecular assay at
follow up (5a and 15a) is also shown for patients 5 and 15.
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A direct role of the mutant c-kit in ligand-independent mast cell
growth, tumorigenesis in vivo, and mast cell differentiation has been
demonstrated in murine systems using either retroviral infection of
hematopoietic progenitor cells with KIT D814V,13 or the
transfection of KIT D814Y cDNA into the murine IL3-dependent mast
cell line IC2.14,15 With regards to human mutations,
only the functional effects of D816V have been investigated.
Transfection of D816V KIT cDNA into myb-transformed
granulocyte-macrophage colony stimulating factor (GM-CSF)-dependent
early murine myeloid cells has been shown to lead to factor
independence, increased survival of immature and mature cells,
tumorigenicity, and a differentiation resembling that previously
noted only in the IC-2 mast cell line.11
It is worth noting that 3 of the 6 patients positive for c-kit
mutations, namely patient 1 with t(8;21) AML-M2, and patients 13 and 15 both with inv(16) AML-M4Eo, showed bone marrow mast cell
(BMMC) involvement. Mast cell differentiation was massive in patient 1, who carried the Asp816Tyr mutation in 100% of the blasts.9,16 Patients 13 and 15 carrying the Asp816Val
mutation had clusters of BMMCs characterized by polar nuclei, a reduced number of small granules, and large empty vacuoles. The remaining three patients positive for Asp816Val did not show any significant increase in BMMCs. The data provided here show that c-kit mutations are not such a rare event in CBF leukemias that display a highly significant correlation for CD117 positivity. In order to assess the
true frequency of c-kit mutations in these AML subtypes, scanning of the whole c-kit gene should be performed on a larger
sample of patients. Further studies will help elucidate whether
c-kit mutations are a secondarily acquired event, as suggested
by their occurrence in a small proportion of blast cells, orwhether
in a few cases they have a primary involvement in leukemogenesis.
Alessandro Beghini
Paolo Peterlongo
Carla B. Ripamonti
Lidia Larizza
Department of Biology and Genetics Medical Faculty
University of Milan Italy
Roberto Cairoli
Enrica Morra
Division of Hematology Niguarda Hospital Milan, Italy
Cristina Mecucci
Hematology and Bone Marrow Transplantation Unit University of
Perugia Italy
| |
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