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Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 596-599
The Reliability and Specificity of c-kit for the Diagnosis
of Acute Myeloid Leukemias and Undifferentiated Leukemias
By
M.C. Bene,
M. Bernier,
R.O. Casasnovas,
G. Castoldi,
W. Knapp,
F. Lanza,
W.D. Ludwig,
E. Matutes,
A. Orfao,
C. Sperling, and
M.B. van't Veer for the European Group for the Immunological
Classification of Leukemias (EGIL)
From the GEIL-Laboratoire d'Immunologie, Faculte de Medicine, Nancy,
France; the Institute Jules Bordet, Brussels, Belgium; the Service
d'Hematologie, Dijon, France; the Institute of Haematology, University
of Ferrara, Ferrara, Italy; the Robert-Rossle-Clinic Charite, Humboldt
University of Berlin, Berlin, Germany; and the Academic Department of
Haematology and Cytogenetics, Royal Marsden Hospital, London, UK.
 |
ABSTRACT |
We document findings on c-kit (CD117) expression in 1,937 pediatric
and adult de novo acute leukemia cases, diagnosed in five single
European centers. All cases were well characterized as to the
morphologic, cytochemical, and immunologic features, according to the
European Group for the Immunological Classification of Leukemias
(EGIL). The cases included 1,103 acute myeloid leukemia (AML), 819 acute lymphoblastic leukemia (ALL), 11 biphenotypic acute leukemia
(BAL), and 4 undifferentiated (AUL). c-kit was expressed in 741 (67%)
AML cases, regardless of the French-American-British (FAB) subtype, one
third of BAL, all four AUL, but only in 34 (4%) of ALL cases. The
minority of c-kit+ ALL cases were classified as: T-cell
lineage (two thirds), mainly pro-T-ALL or T-I, and B lineage (one
third); cells from 62% of these ALL cases coexpressed other myeloid
markers (CD13, CD33, or both). There were no differences in the
frequency of c-kit+ AML or ALL cases according to age
being similar in the adult and pediatric groups. Our findings
demonstrate that c-kit is a reliable and specific marker to detect
leukemia cells committed to the myeloid lineage, and therefore should
be included in a routine basis for the diagnosis of acute leukemias to
demonstrate myeloid commitment of the blasts. c-kit expression should
score higher, at least one point, in the system currently applied to the diagnosis of BAL, as its myeloid specificity is greater than CD13
and CD33. Findings in ALL and AUL suggest that c-kit identifies a
subgroup of cases, which may correspond to leukemias either arising
from early prothymocytes and/or early hematopoietic cells, both
able to differentiate to the lymphoid and myeloid pathways.
| |
INTRODUCTION |
THE c-KIT PROTO-ONCOGENE encodes a
145-kD tyrosine kinase transmembrane receptor, which plays
a key role in hematopoiesis, as it is the receptor for the stem cell
factor (SCF). Expression of c-kit can be detected by immunostaining
with monoclonal antibodies (MoAb) clustered under CD117 or
by Northern blot or reverse transcriptase-polymerase chain reaction
(RT-PCR), which allows detection of c-kit transcripts.
c-kit is expressed in a minority (<5%) of bone marrow progenitor
cells, half of which express CD34 and some appear to be committed to
the myeloid lineage.1-3 A variety of human leukemia cell
lines, in particular those committed to the myeloid, erythroid, and
megakaryoblastic lineages or with mutipotential capacity are also c-kit
positive.2,4,5 In addition, c-kit expression has been
documented in a minority of early human thymocytes located at the
subcapsular cortex and at the intralobular septa of the thymus, which
have a CD7+CD4-CD8-CD3-
phenotype, and are able to differentiate in vitro to the lymphoid and
nonlymphoid lineages.2 Similarly, bone marrow
CD34+CD2+CD7+ stem cells are able
to differentiate towards the T-cell pathway and such differentiation is
enhanced by the c-kit ligand.6 These findings suggest that
CD34+ CD7+ c-kit+ cells are indeed
pluripotent lymphohematopoietic cells and that c-kit plays a major role
in early T-cell development.2,6 Similar data have been
reported on murine prothymocytes, which are also c-kit positive and
have germ-line configuration of the T-cell receptor (TCR)  / chain
genes.7 Findings have been controversial as to whether a
minority of bone marrow progenitor B cells express
c-kit.1,8 Using sensitive techniques, reactivity with c-kit
has been detected in 4% of bone marrow CD19+ cells from
some, but not all, normal individuals,8 and although cord
blood CD19+ lymphoid progenitors may have a moderate
expression of the SCF receptor, the antibody reactivity has not been
assessed in these samples.9 In addition, c-kit is expressed
on a small fraction of natural killer CD56+ cells, which
display both forms, the high and intermediate affinity of the
interleukin-2 receptor.10
In parallel to studies in normal hematopoietic cells, there have been a
number of reports on c-kit expression in acute leukemia cells. Most of
them have shown that a substantial proportion of cases, particularly
acute myeloid leukemias (AML), are c-kit positive (for review, see
Muroi et al11). Although the reactivity with c-kit has been
mainly confined to the myeloid leukemias, its specificity for the
myeloid lineage has been questioned, as some reports have observed
expression of c-kit in few cases of early T-acute lymphoblastic leukemia (ALL)12 and weak reactivity in some B-cell lineage ALL using sensitive techniques.3 A letter by Muroi et
al11 summarized the reported findings on c-kit expression
in acute leukemias and based on the evidence that c-kit was, as a rule, negative in ALL, the investigators concluded that c-kit is a specific marker for the myeloid lineage. However, the number of ALL cases included in all of these reports was relatively low, with a total of
189.
On the EGIL proposals,13 the members did not dispute the
myeloid specificity of c-kit, but felt that its reactivity needed to be
tested on a large scale basis to validate or not the specificity of
this marker, as well as its sensitivity for the myeloid lineage.
We report here findings obtained with MoAb against c-kit in a large
group of cases with acute leukemias investigated in five European
institutions or working groups and discuss the reliability of this
marker for the diagnosis of AMLs.
| |
MATERIALS AND METHODS |
Patients.
Material from 1,937 acute leukemia patients diagnosed in institutions
from five European countries has been analyzed. Most of the patients
had been enrolled on national acute leukemia trials. The diagnosis was
made by (1) standard morphology and cytochemistry of peripheral blood
and bone marrow films according to the French-American-British (FAB)
criteria14 and (2) immunophenotyping using a comprehensive panel of MoAbs against myeloid and lymphoid-associated antigens, as
proposed by the EGIL group.13 Cases with a diagnosis of
blast transformation of chronic myeloid leukemia and/or other
myeloproliferative disorder were excluded. Of 1,937 patients, 1,211 were adults and 726 children. All of the samples contained over 30% of
blasts and usually more than 50%.
Immunological markers.
Peripheral blood and/or bone marrow mononuclear cells were
isolated by a gradient density centrifugation and washed twice in
Hank's balanced salt solution before immunophenotyping. The MoAb YB5B8
(Immunotech, Marseille, France) against the c-kit receptor was used in
1,665 samples and the MoAb 95C3 (Immunotech) in the remaining 272. Fifty samples were tested with these two MoAbs and with 102B4E1 (a gift
from Dr Buhring, Tubingen). Negative controls included the
omission and/or substitution of the MoAb by a mouse Ig of a
matched isotype. Analysis was performed by flow cytometry with an
indirect immunofluorescence technique using a fluorescein
isothiocyanate (FITC)-conjugated antimouse Ig as second layer. The
blast population was gated using morphologic parameters (ie, size of
cells as measured by forward scatter and granularity as measured with
side scatter signals). A case was considered positive when over 20% of
blasts reacted with the MoAb according to the EGIL
criteria.13
The 1,937 cases were distributed in the following immunologic
subgroups: (1) ALL (n = 819), 612 B-cell lineage and 207 T-cell lineage. The B- and T-cell lineage ALL were further subclassified in
four subtypes according to the level of differentiation of the
blasts.13 Briefly, these comprised in B-cell lineage ALL (CD19+, CD79a+, and/or
CD22+; TdT+); B-I (no expression of other
B-cell differentiation antigens); B-II (CD10+); B-III
(cytoplasmic IgM+) and B-IV (cytoplasmic or surface
immunoglobulin light chain+) and, in T-lineage ALL
(CD3+, TdT+), T-I (CD7+); T-II
(CD2+ and/or CD5+ or CD8+);
T-III (CD1a+) and T-IV (membrane CD3+).
(2) AML (N = 1,103) were found in which blasts were positive with one
or more myeloid markers. According to the FAB classification, AML cases
corresponded to 106 M0, 191 M1, 258 M2, 59 M3, 187 M4, 125 M5, 43 M6,
and 13 M7; the FAB subtype was not available in the remaining 121 cases.
(3) Eleven cases were classified as biphenotypic acute leukemia (BAL)
and these comprised nine cases with a B-lymphoid and myeloid phenotype,
one with a T-lymphoid and myeloid phenotype, and one case with
trilineage differentiation; all of the cases had scores >2 for the
myeloid and lymphoid lineages according to the proposed
criteria.13 BAL was defined when blasts scored over 2 points for the myeloid lineage and one for the lymphoid lineages. The
number of points assigned to each marker is based on the specificity of
the marker for the myeloid and lymphoid lineages, as shown in
Table 1. We did not assign myeloid points to c-kit reactivity, as the aim of this study was to test the specificity of c-kit for the myeloid lineage.
(4) The remaining four cases were considered as acute undifferentiated
leukemia (AUL), as they could not be classified by cytochemistry and by
the expression of lymphoid and myeloid markers; blast cells from these
four cases were only positive with CD38, HLA-DR, CD7, CD34,
and/or TdT antibodies.
| |
RESULTS |
Blast cells from 783 of the 1,937 cases (40%) were c-kit positive.
These included all four AUL, two thirds of AML, and one third of BAL,
whereas only a minority of ALL were c-kit positive (Table 2).
Results on the reactivity with c-kit in the AML group according to the
FAB subtypes are shown in Table 3. A
varying proportion of cases with all FAB subtypes were c-kit positive
with the higher percentage of positive cases in the subtypes with
a myeloid component: M0, M1, and M2, while only one third of M5 and
M7 expressed c-kit (Table 3). Of the four cases with BAL,
which were c-kit positive, two corresponded to the only ones with a
T-lymphoid and myeloid component (one case) and to the case with
trilineage differentiation, while the other two cases had a mixed
B-lymphoid and myeloid phenotype.
Only 4% of ALL cases were c-kit positive, and of these, two thirds
were T-lineage ALL and the other third B-lineage ALL, representing, respectively, 11% c-kit positive cases within T-ALL and 2% c-kit positive in the B-cell lineage ALL group. The stage of maturation and
immunophenotypic characteristics of the c-kit positive ALL are
summarized in Table 4. Half of the T-ALL
corresponded to pro-T-ALL (T-I) and the other half had a more mature
T-cell immunophenotype (TII-TIV). All of the c-kit positive B-cell
lineage ALL had either a common-ALL (B-II) or pre-B-ALL (B-III)
immunophenotype, and only one case had a mature B-ALL (B-IV)
immunophenotype. Cells from 21 of the 34 c-kit positive cases (62%)
expressed one or two other myeloid markers: CD13, CD33, or both, but
none qualified as BAL. Of these 21, 13 were T-lineage ALL and the other
seven were B-lineage ALL (Table 4).
In the 50 cases in which the three MoAb against c-kit were
investigated, there were no significant differences in the proportion of c-kit positive cells.
Overall, there were no substantial differences regarding the incidence
of c-kit positive cases in pediatric and adult leukemias, although the
proportion was slightly higher in adult AML, 69% c-kit+
(613 of 883) versus 58% (128 of 220) in pediatric AML cases. In ALL,
4.6% (23 of 501) of pediatric samples and 3.4% (11 of 318) of adult
samples, respectively, were c-kit positive. Considering BAL, c-kit
expression was seen in both, children (1 of 5 [20%]) and adults (2 of 6 [30%]) and all four AUL were adults.
There was a correlation between expression of CD34 and c-kit in AML, as
76% of cases either expressed both antigens or were negative with the
two MoAb, while the remaining 24% of cases expressed only one of the
two antigens. In contrast, there was no evidence that
c-kit+ AML had a higher frequency of lymphoid antigen
expression, being the proportion of cases positive with CD2 (9%), CD7
(25%), CD10 (1%), and CD19 (7%) similar to c-kit negative cases.
| |
DISCUSSION |
Our findings, based on a large number of well characterized acute
leukemia cases, clearly establish the high specificity of c-kit for
leukemic cells committed to the myeloid lineage and thus, support its
value as a diagnostic reagent in the characterization of acute
leukemias. Although the sensitivity of c-kit to detect AML seems to be
slightly lower than CD13 and CD33, particularly in cases with a
monocytic component, its specificity is significantly higher, as the
latter two markers are expressed in a significantly larger proportion
of ALL cases (for review, see Drexler et al15). When
considering AML, our data show that c-kit is more often expressed in
CD34+ AML, but do not support that it is preferentially
associated with a particular FAB subtype. Although c-kit is more often
positive in cases with myeloid/granulocytic differentiation (eg,, M0 to M2) compared with those with proliferation of monoblasts, it cannot be
taken as a marker discriminatory of the various AML subtypes.
The analysis of the immunophenotypic characteristics of the minority of
c-kit positive ALL showed that two thirds of these cases were also
positive with one or two myeloid markers and/or corresponded to
pro-T-ALL. Thus, c-kit seems to identify a minor group of ALL, which
has either early T-cell features and/or expresses other myeloid
antigens. This suggests that such leukemias arise from primitive
progenitor cells or represent the leukemic counterpart of the normal
prothymocyte, which is c-kit+, CD7+. Indeed,
the four c-kit+ ALL cases reported by Nishi et
al12 had myeloid antigen expression, only two expressed CD3
in the cytoplasm, and all had the TCR / chain genes in germ line
configuration, features that fit well with a very early hematopoietic
cell.
Of interest is our finding that all four cases with undifferentiated
acute leukemia were c-kit positive. None of these cases expressed
myeloid or lymphoid differentiation markers, but most were
CD7+,CD34+. Such an immunophenotype is similar
to that found in a small proportion of bone marrow and/or early
thymic cells2,6 able to differentiate to myeloid and
lymphoid cells and perhaps represent an earlier step in differentiation
than that of the c-kit+ pro-T-ALL.
In summary, MoAb recognizing the c-kit receptor appear to be useful
reagents recommended to be routinely used in the panel of markers for
the diagnosis of acute leukemias to demonstrate or support the myeloid
commitment of the blasts in both pediatric and adult patients. Due to
its now well established specificity for the myeloid lineage, the c-kit
marker should score for the myeloid lineage at least one point in the
scoring system for the diagnosis of biphenotypic acute leukemias
proposed by the EGIL.13
| |
FOOTNOTES |
Submitted December 8, 1997;
accepted March 11, 1998.
Address reprint requests to E. Matutes, MD, PhD, Academic Department of
Haematology and Cytogenetics, The Royal Marsden Hospital, Fulham Road,
London SW3 6JJ, UK; e-mail: estella{at}icr.ac.uk.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract