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REVIEW ARTICLE
From the Institute of Hematology, University of
Perugia, Italy; and the LRF Immunodiagnostics Unit, John Radcliffe
Hospital, Oxford, England.
Acquired chromosomal anomalies (most commonly translocations) in
lymphoma and leukemia usually result in either activation of a
quiescent gene (by means of immunoglobulin or T-cell-receptor promotors) and expression of an intact protein product, or creation of
a fusion gene encoding a chimeric protein. This review summarizes current immunocytochemical studies of these 2 categories of oncogenic protein, with emphasis on the clinical relevance of their detection in
diagnostic samples. Among the quiescent genes activated by rearrangement, expression of cyclin D1 (due to rearrangement of the
CCND1 [BCL-1] gene) is a near-specific marker
of t(11;14) in mantle cell lymphoma; BCL-2 expression
distinguishes follicular lymphoma cells from their nonneoplastic
counterparts in reactive germinal centers and appears to be an
independent prognostic marker in diffuse large cell lymphoma; and
TAL-1 (SCL) expression identifies T-cell acute
lymphoblastic neoplasms in which this gene is activated. The protein
products of other genes activated by chromosomal rearrangement have a
role as markers of either lineage (eg, PAX-5 [B-cell-specific activator protein] for B cells, including B-lymphoblastic neoplasms), or maturation stage (eg, BCL-6 for germinal-center and activated B
cells and MUM-1/IRF4 for plasma cells). Currently, no hybrid protein
encoded by fusion genes is reliably detectable by antibodies recognizing unique junctional epitopes (ie, epitopes absent from the
wild-type constituent proteins). Nevertheless, staining for promyelocytic leukemia (PML) protein will detect acute PML with t(15;17) because the microspeckled nuclear labeling pattern for PML-RAR Translocations, deletions, and other nonrandom
chromosomal abnormalities1,2 play a central role in the
pathogenesis of many human hematologic malignant diseases. A growing
number of studies are revealing the ways in which these chromosomal
alterations affect specific genes, such as those encoding nuclear
transcription factors. However, any gene implicated in the neoplastic
process can act only through the protein it encodes. Many of the
consequences of chromosomal changes with respect to abnormal protein
expression have been inferred indirectly by analysis of messenger RNA
(mRNA) transcription, but it is clear that protein and mRNA levels do not always correlate. For example, germinal-center B cells appear to
contain BCL-2 message but little protein,3,4
and the same is true for TAL-1 in erythroid
cells.5 Many examples of the opposite combination (high
protein and little or no message) also exist, such as BCL-2 in mature
lymphocytes6,7 and elastase in mature myeloid
cells.8 Antibody-based detection of the protein is
therefore required, but this frequently cannot be done because of a
lack of suitable reagents. Consequently, we are often ignorant not only
about patterns of expression of oncogenic proteins in hematologic
neoplasms but also about possible abnormalities in the distribution and
subcellular localization of these proteins.
Most of the currently recognized genetic alterations in human leukemias
and lymphomas result in either activation of a quiescent gene or
creation of a hybrid gene encoding a chimeric protein. Table
1 summarizes the genetic abnormalities
that have been studied using antibodies specific for the protein
products of genes involved in such rearrangements. We here review the
immunocytochemical studies that have been done with these antibodies
and assess, for each protein, whether abnormalities demonstrable by
immunocytochemistry are of clinical value in determining diagnosis or
predicting prognosis. Immunocytochemical findings that are of value are
discussed below, whereas those for which no clear clinical applications
have been observed are described briefly in Table
2.
The CCND1 (BCL-1) gene and its protein product
(cyclin D1)
CCND1 (BCL-1) gene.
The (11;14)(q13;q32) translocation,9 an anomaly often
found in mantle cell (centrocytic) lymphoma10,11 and
occasionally in other B-cell neoplasms, notably
myeloma,12,13 juxtaposes the CCND1
(BCL-1) locus encoding cyclin D1 on chromosome 11 to an
immunoglobulin-enhancer sequence on chromosome 14.9 The CCND1 gene is transcriptionally silent in normal
lymphohemopoietic tissues14,15; thus, expression of the
protein may promote neoplastic cell proliferation by perpetuating the
transition from G1 to S.16
Antibodies to cyclin D1.
Several antibodies recognizing cyclin D1 have been described (Table
3),14-18 but
hematopathologists know that immunocytochemical detection of cyclin D1
in routinely processed tissues is not always easy.19,20 It
is possible that cyclin D1 is so closely associated with other
molecules in the nucleus that epitopes are masked. Whatever the cause
of the difficulty, reliable staining can usually be obtained by using
an optimized technique (eg, by incubating the antibody overnight with
sections previously subjected to microwave heating in the presence of
EDTA), as described in detail elsewhere.19-21
Cyclin D1 expression in normal tissues. Cyclin D1 is not detectable by immunocytochemistry in normal lymphohemopoietic tissues,14 although a variety of stratified squamous epithelia are positive for cyclin D1.14 Cyclin D1 in lymphoid neoplasia.
Most mantle cell lymphomas express cyclin D1,22-25
although the staining intensity and the percentage of positive cells
differ from case to case.15 Immunostaining is usually seen
in a diffuse pattern in cell nuclei,15,24 but cytoplasmic
positivity is also occasionally observed.17 The blastoid
form of mantle cell lymphoma,26 characterized by frequent
rearrangement of the CCND1 (BCL-1) gene, a high
mitotic index, and a poor prognosis,27 shows no difference
in the pattern or frequency of cyclin D1 staining.28 Expression of cyclin D1 has also been observed in cases of multiple lymphomatous polyposis (Figure 1), the
intestinal form of mantle cell lymphoma.11
Cyclin D1 expression is not completely specific for mantle cell lymphoma29,30: it has been found in plasmacytoma/myeloma, especially in cases with t(11;14)31,32; in sporadic cases of B-cell chronic lymphocytic leukemia (B-CLL), some of which show t(11;14) and CCND1 rearrangement,33 and in hairy cell leukemia, although levels of cyclin D1 are lower than in mantle cell lymphoma and no CCND1 (BCL-1) gene rearrangements are detected.33,34 Expression of CCND1 (BCL-1) mRNA due to t(11;14) has been found in some cases of splenic marginal zone lymphoma,13 but no protein has been detected by immunohistological methods in this disease.35 Clinical applications of cyclin D1 immunostaining. Detection of cyclin D1 by immunohistochemistry can be added to other criteria for the diagnosis of mantle cell lymphoma,11,30,36 particularly when a poor biopsy or an unusual growth pattern hinders recognition of the disease. Because mantle cell lymphoma has a range of morphologic features (from a small cell tumor to a blastoid proliferation11,26) and growth patterns (diffuse, nodular, or mantle zone23,37), a near-specific marker is clearly valuable, particularly because survival in this disease is significantly worse than that in other small cell B-cell lymphomas.11,37,38 In addition, cyclin D1 immunostaining may distinguish multiple lymphomatous polyposis from other indolent intestinal lymphomas, and the blastoid variant of mantle cell lymphoma (BCL-1 positive) from B-lymphoblastic lymphoma/leukemia (BCL-1 negative).28 Cyclin D1 immunostaining has also been used to identify cases of mantle cell lymphoma in a leukemic phase (a poor prognostic condition) and to differentiate them from other atypical chronic lymphoproliferative disorders.39,40 The BCL-2 gene and its protein product BCL-2 gene. The (14;18) chromosomal translocation in follicular lymphoma involves the BCL-2 gene at the chromosome 18 breakpoint, which encodes a 26-kd protein with limited homology to an Epstein-Barr viral protein (BHRF-1).41 Because breakpoints occur in the 3' untranslated region, full-length protein is expressed after juxtaposition of the gene to the immunoglobulin heavy-chain promoter.41 Extensive studies have documented the role of BCL-2 in blocking apoptosis in many cell types and in response to a variety of stimuli.41 Many cellular and viral homologues have also been identified. Antibodies to BCL-2. Mouse and hamster monoclonal antibodies (mAbs) to BCL-2 protein have been described (Table 3).7,42 One of these, the mouse monoclonal reagent designated BCL-2/124,7 is used in many of the immunocytochemical studies discussed below. BCL-2 in normal tissues. BCL-2 is associated with mitochondria and cell membranes43 and is widely distributed in both hemopoietic and nonhemopoietic cells.7,42 However, BCL-2 is absent from B-lymphoid cells in the germinal centers of B-cell follicles and from cortical thymocytes,7,44-46 and it ceases to be detectable when cells are transformed (eg, by mitogens).7 BCL-2 in hematologic neoplasia.
BCL-2 protein is expressed in most cases of follicular
lymphoma,47 both in the majority with t(14;18) and in many
without it.48,49 However, a few cases lack both protein
expression and rearrangement.50 BCL-2 protein is also
expressed in many lymphoid and myeloid
neoplasms,7,46,51-56 although it is usually absent or
expressed at low levels in Burkitt lymphoma53,57 and
anaplastic lymphoma kinase (ALK)-positive anaplastic large cell
lymphoma (ALCL),58,59 possibly because of the high rate of
cell proliferation.60 BCL-2 protein is also often absent or present at low levels in large B-cell tumors at extranodal sites,
including the gastrointestinal tract.51,61,62 In contrast, lymph node-based B-cell neoplasms are commonly positive for
BCL-2.54 Furthermore, although low-grade mucosa-associated
lymphoid tissue (MALT) lymphomas of the gastrointestinal tract are
BCL-2 positive,61 they often contain areas of larger cells
that lack BCL-2 (Figure 2A),63,64 probably
representing early transformation to large cell neoplasms. This may be
relevant to observations that large B-cell neoplasms arising from
MALT are BCL-2 negative51 and that proliferative
markers in nodal lymphomas are inversely related to expression
of BCL-2.60
In follicular lymphomas,47 BCL-2 expression may also be heterogeneous, and the BCL-2-negative cells tend to be centroblasts (large noncleaved cells) rather than centrocytes (Figure 2B). As a result, cases at the aggressive end of the morphologic spectrum may appear to be BCL-2 negative when, in reality, few cells express the protein. This "pseudonegative" pattern is accentuated by the tendency of centrocytes to migrate away from neoplastic follicles so that large nodules of BCL-2-negative centroblasts are observed, with intervening smaller neoplastic cells that can be mistaken for normal cells (Figure 2B).47 It is possible that the BCL-2-negative large cell component is more sensitive to chemotherapy than is the small cell component, which may therefore persist and account for the indolent progression of the disease. BCL-2 protein is found in Reed-Sternberg cells in one third to three fourths of all biopsy specimens from patients with Hodgkin disease (HD),45,65-67 including a few who have also had follicular lymphoma,68 but this presumably reflects its ubiquitous presence in lymphoid cells. However, the neoplastic cells of lymphocyte predominance HD (lymphocytic and histiocytic [L&H] or popcorn cells) tend to be BCL-2 negative,69,70 thereby illustrating the distinct nature of this HD subtype.11 Clinical applications of BCL-2 immunostaining.
Although the ubiquitous distribution of BCL-2 protein limits its value
for diagnosis, it is widely used for distinguishing reactive lymphoid
follicles, which are BCL-2 negative, from neoplastic follicles and
proliferation centers (found in chronic lymphocytic leukemia46,71-73), both of which are usually BCL-2
positive. In MALT lymphoma, for example, the reactive lymphoid
follicles characteristically associated with this tumor (which may be
confused with follicular lymphoma) are clearly negative (Figure
2A),64 at least until they have undergone follicular
colonization by neoplastic cells.74 A similar phenomenon
has been observed in mantle cell lymphomas that localize around
germinal centers (Figure
3C).52
BCL-2 may also be of value as a marker for identifying infiltration by follicular lymphoma cells in bone marrow trephine biopsy specimens.75,76 Aggregates of normal or reactive lymphoid cells often stain only weakly (although T cells label more strongly than B cells) and have nondescript nuclear morphologic features. In contrast, follicular lymphoma cells show strong cytoplasmic BCL-2 labeling, which tends to emphasize their characteristic cleft nuclear morphologic features (Figure 2B), and this is often a valuable adjunct to the classic criterion of a paratrabecular infiltration pattern. It is also possible that cases of "Burkitt-like" lymphoma can be distinguished from epidemic/sporadic Burkitt lymphoma by the expression of BCL-2 protein,57 as can cases of lymphoblastic lymphoma/leukemia,77 although further studies of this issue are needed. It has been suggested that the presence of high levels of BCL-2 protein promotes survival of neoplastic cells78 or confers drug resistance79 (or both) and thus is a marker of a poor prognosis. Many clinical studies have sought evidence of such a correlation, and an association between higher cellular BCL-2 levels and poorer disease-free survival at periods up to 10 years was found in several studies of diffuse large cell lymphoma (DLCL).80-86 There is also some evidence for a prognostic influence of BCL-2 levels in acute myeloid leukemia.87-91 However, for other hematologic malignant diseases (HD,92 follicular lymphoma,84,93,94 chronic lymphocytic leukemia,95,96 and acute lymphoblastic leukemia [ALL]97-99), the data are limited or equivocal. Diffuse lymphomas therefore represent the most promising area for future studies of BCL-2 expression and offer the longer-term prospect of strategies for specifically inhibiting BCL-2.86 However, few if any oncologists currently take BCL-2 levels into account when treating individual patients, and this variable has not been used in any controlled trials to assign patients with lymphoma to more aggressive treatment protocols. The BCL-6 gene and its protein product BCL-6 gene. Studies in knockout mice found that BCL-6 protein is required for germinal-center formation, antibody-affinity maturation, and T-helper-2-mediated responses.100 BCL-6 appears to inhibit differentiation of germinal-center B cells toward plasma cells by binding to signal transducers and activators of transcription 3, thereby preventing the expression of Blimp-1 (a major regulator of plasma cell development).101 Chromosomal translocations involving the 5' noncoding domain of the BCL-6 gene102 at band 3q27 are observed in about 40% of diffuse large B-cell lymphomas103 and 10% to 15% of follicular lymphomas,103 juxtaposing the gene to promoters from a variety of partner chromosomes (most commonly in immunoglobulin chain loci). Mutations of the regulatory part of the BCL-6 gene are virtually absent in ALL and mantle cell lymphoma, but they occur frequently in germinal-center and postgerminal-center lymphomas, including follicular lymphomas, DLCLs, and Burkitt lymphomas.104 However, mutations of the BCL-6 gene have also been found in normal germinal-center B cells,105 and it is not clear what role they play in lymphomagenesis.Antibodies to BCL-6. Two mAbs (PG-B6p and PG-B6a) have been raised against a recombinant BCL-6 protein (Table 3). PG-B6p, which recognizes a formalin-resistant amino-terminal epitope, labels routinely processed biopsy specimens.106 BCL-6 in normal tissues. In lymphoid tissues, BCL-6 protein is expressed in germinal-center B cells in secondary follicles (Table 3 and Figure 3A)106-111 in both the dark (centroblast-rich) and light (centrocyte-rich) zones.106-110 It is also detectable in a few CD4-positive T cells, both in the germinal centers and in interfollicular areas,107,108 and in perifollicular CD30+ lymphoid cells.107 In addition, BCL-6 protein is expressed in thymocytes, mainly in the cortex.112 Outside the lymphohemopoietic system, expression of BCL-6 has been observed in squamous epithelia.106,113 In all positive cells, BCL-6 protein localizes to the nucleus in a diffuse or microgranular pattern.106-108,110 BCL-6 in lymphoid neoplasia. Strong nuclear expression of BCL-6 occurs frequently in follicular lymphomas, paralleling its presence in germinal-center cells, their normal counterpart. BCL-6 expression is also found in most Burkitt lymphomas and diffuse large B-cell lymphomas (Figure 3B), regardless of whether the gene is rearranged.106-108,110,114 In lymphomas associated with human immunodeficiency virus, expression of BCL-6 and expression of the Epstein-Barr viral protein LMP1 appear to be mutually exclusive.115 Neoplasms of B cells unrelated to germinal centers (eg, B-cell precursor malignant diseases, B-CLL, mantle cell and marginal zone lymphomas, and hairy cell leukemia) consistently lack BCL-6 protein (Figure 3C),106 in keeping with its absence from the putative normal counterparts of these neoplasms.11,116 Among T-cell lymphomas, BCL-6 expression has been detected in about 50% of ALCLs117 and T-cell lymphoblastic lymphomas.112 Reed-Sternberg cells in classic HD are usually BCL-6 negative, but the tumor cells (L&H cells) in lymphocyte predominance HD are strongly positive (Figure 3D),118 in keeping with their probable germinal-center origin.69,119Clinical applications of BCL-6 immunostaining. BCL-6 is a valuable marker of B cells of germinal-center origin.106,110,120 BCL-6 immunostaining, used in conjunction with BCL-2, may be useful in characterizing nodular lymphoid regions, since these can represent neoplastic germinal centers (indicative of follicular lymphoma), trapped residual germinal centers (eg, in MALT and mantle cell lymphomas; Figure 3C), or proliferation centers (in B-CLL).121 Labeling for BCL-6 may also help in the recognition of lymphocyte predominance HD (Figure 3D).118,122 The MUM1/IRF4 gene and its protein product MUM1/IRF4 gene. The 14q+ cytogenetic anomaly in multiple myeloma represents a cryptic t(6;14)(q25;p32) that juxtaposes the immunoglobulin heavy-chain locus to a gene known as MUM1 or IRF4.123 The MUM1/IRF4 gene encodes a transcription factor thought to play a key role in lymphoid development, since IRF4-deficient mice have a block in peripheral B-cell maturation (absence of germinal centers and plasma cells) associated with a lack of cytotoxic T-cell responses.124 Antibody to MUM1/IRF4. A recently generated mAb (MUM1p)125 against human MUM1/IRF4 protein is suitable for immunostaining routinely prepared paraffin sections and for Western blotting, in which it detects a 50-kd band of expected molecular weight. MUM1/IRF4 in normal tissues. In normal lymphoid tissue (Table 3), MUM1/IRF4 protein is detected mainly in plasma cells and in a small number of germinal-center B cells, which are usually BCL-6 negative and nonproliferating (Ki67 negative) and found mainly in the light zone of the germinal center.125 In addition, MUM1/IRF4 is expressed in a small percentage of T cells and in most perifollicular CD30-positive cells,125 in keeping with its expression by peripheral blood T cells after stimulation with phytohemagglutinin.125 In all positive cells, MUM1/IRF4 protein expression is primarily nuclear and shows a microgranular and diffuse pattern, with sparing of nucleoli.125 MUM1/IRF4 in lymphoid neoplasia. In accordance with its expression at late stages of B-cell differentiation and after T-cell activation, MUM1/IRF4 protein is strongly expressed in lymphoplasmacytic lymphoma/immunocytoma, about 75% of diffuse large B-cell lymphomas, primary effusion lymphomas,126 HD, multiple myeloma, and ALCL.125,127,128 Clinical applications of MUM1/IRF4 immunostaining.
Because of the restriction of MUM1/IRF4 to late-stage B cells, it is
potentially valuable (used in combination with other plasma cell
markers, such as CD138) for recognizing myelomas (Figure 4A). Furthermore, its consistent
expression in neoplastic cells in HD (Figure 4B) can be of diagnostic
help when the staining highlights Reed-Sternberg and Hodgkin cells in a
tissue biopsy specimen (eg, of bone marrow).
The PAX-5 gene and its protein product PAX-5 gene. The PAX-5 gene (a member of the paired-box PAX gene family) encodes the transcription factor B-cell-specific activator protein (BSAP), which plays a key role in B-lymphoid development129 and is also involved in the embryonic development of the central nervous system and testis. In the t(8;14)(p13;q32), which is characteristic of small lymphocytic lymphoma with plasmacytoid differentiation (immunocytoma), the PAX-5 gene (on 9p13) is juxtaposed to the immunoglobulin heavy-chain gene (on 14q32).130 Antibodies to PAX-5. A polyclonal antibody to PAX-5 has been described,131 and a mAb is available commercially (Transduction Laboratories, Lexington, KY; Table 3). Both detect PAX-5 protein in paraffin-embedded samples. Expression of PAX-5 in normal tissues. In tissue sections, PAX-5 protein can be stained in B-cell follicles but not plasma cells.131 Unlike B-cell-associated transcription factors such as BCL-6 and MUM1, which are also expressed in activated T cells,106,107,125 PAX-5 appears to be B-cell specific131 (Table 3). Experimental studies have shown that PAX-5 protein is expressed in B-lymphoid precursors, but no data on direct immunostaining in human bone marrow have been reported. Expression of PAX-5 in lymphohemopoietic neoplasms. PAX-5 has been found in many B-cell lymphomas (with the strongest expression in follicular, mantle cell, and DLCLs)131 but not in T-cell neoplasms. Clinical applications of PAX-5 immunostaining.
PAX-5 may prove to be a valuable diagnostic marker in paraffin-embedded
biopsy specimens of B-lymphoblastic neoplasms because it is expressed
strongly in such samples and is negative in T-cell lymphoblastic
proliferations (Figure 5A; B.F.,
unpublished data, 2001). HD sometimes mimics ALCL, and PAX-5 may be
useful in such cases because Reed-Sternberg cells are usually
positive132 (Figure 5B), whereas ALCLs (both ALK positive
and ALK negative) are consistently negative for PAX-5.
The TAL-1 gene and its protein product TAL-1 gene.
The TAL-1 gene (also known as SCL or
TCL-5)133 at 1p32 encodes a 42-kd nuclear
protein134 that is essential for mammalian hematopoiesis133 and normal yolk sac
angiogenesis.135 Structural alterations in the
TAL-1 gene represent the most frequent molecular lesions in
T-cell ALL (T-ALL).1,133 In up to 25% of childhood cases,
a submicroscopical 90-kilobase-pair deletion on the 5' side of the
gene133 brings it under the influence of promoters for the
SIL gene. Much less commonly, the gene is rearranged by a
chromosome translocation; this is usually t(1;14)(p32;q11), which
associates the gene with the TCR Antibodies to TAL-1. Several mAbs suitable for immunocytochemical detection of TAL-1 have been described (Table 3).137,138 TAL-1 in normal tissues.
Studies of TAL-1 protein or TAL-1 mRNA found that the gene
is expressed in some, but not all, hemopoietic lineages (notably, erythroid precursors, megakaryocytes, and mast cells; Figure
6A),137,139,140 but it is
not detectable in even the most immature T cells (thymocytes and
CD2-positive precursor lymphoid cells in fetal liver).141 TAL-1 immunostaining is localized to the nucleus (Figure
6A-C),137 characteristically in the form of small dots
(Figure 6C),137 whose number is greater than that of
PML-positive structures. In mitotic cells, TAL-1 is consistently
cytoplasmic.137
TAL-1 in hematologic neoplasia. The TAL-1 gene is activated in about one fourth of all cases of T-ALL, but the link with expression of TAL-1 protein remains unclear. In several T-ALL lines, mRNA and/or protein was found in the absence of detectable gene rearrangement,137,142 and TAL-1 mRNA has been detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in most cases of T-ALL.143,144 However, this may derive from normal monocytes and T cells in the samples145: the results of an immunocytochemical study suggested that TAL-1 protein is only rarely expressed by leukemic cells in T-ALL when the gene is not rearranged.146 Clinical applications of TAL-1 immunostaining. In a study by Chetty et al,147 samples from approximately 50% of T-ALL cases showed nuclear labeling, but the investigations were done in paraffin-embedded tissue, on which the available mAbs do not provide clean labeling. However, immunocytochemical labeling of fresh T-ALL samples that were also studied with molecular biologic techniques suggested that cases in which the TAL-1 gene is rearranged can be detected by immunocytochemistry.146 There appears to be no correlation between TAL-1 gene rearrangement and clinical behavior in T-ALL.148
Several chromosomal translocations cause fusion of unrelated genes rather than overexpression of intact quiescent genes, and these hybrid genes encode tumor-associated chimeric proteins.1,2 This situation has reawakened interest in producing tumor-specific antibodies, but unfortunately, antibodies specific for the novel junctional regions in these chimeric proteins have proved to be difficult to raise. In addition, genes may break at different points and thus give rise to more than one fusion protein, with different junctional regions. In spite of these obstacles, progress has been made by using antibodies directed against nonjunctional parts of chimeric proteins, since such antibodies can detect relocalization (eg, PML) or de novo expression induced by gene fusion (eg, ALK). The (15;17) translocation and its variants The PML and RAR Antibodies to PML.
Most PML isoforms and PML-RAR PML in normal tissues.
Wild-type PML protein is expressed ubiquitously, but levels vary
greatly according to cell type.154,158-160 PML protein is
localized to discrete nuclear dots (average, 10 dots/nucleus) not
associated with nucleoli (Figure
7A).154,156,161-163 The
diameter of these dots ranges from 0.5 to 1 µm,162 and
they correspond to nuclear domains (PML oncogenic domains
[PODs])164,165 reorganized previously by electron
microscopy as "nuclear bodies"166 and by
immunocytochemistry as "nuclear dots" or "nuclear domain
10."167 These macromolecular protein-rich complexes are
tightly bound to the nuclear matrix155,163,164 and are
known to contain several other proteins, including Sp100, NDP52,
PIC1/SUMO-1, and Int-6.165,168-174 Progressive accretion
of proteins gives rise to a characteristic ringlike
appearance,154,156,162 especially in cells
overexpressing PML.
PML in hematologic neoplasia.
In leukemias other than APL (and in lymphomas), PML labeling
consistently shows a wild-type speckled pattern (Figure 7A, right). In
cells containing the PML-RAR Clinical applications of PML immunostaining.
APL can be diagnosed rapidly by showing the microgranular PML
immunocytochemical labeling pattern (Figure 7B).176-180
This appearance is specific for APL with t(15;17), since the variants
t(11;17) and t(5;17) do not disrupt the wild-type speckled
pattern.181-184 Immunostaining must be done on fresh
samples (smears, cytospin preparations, or frozen sections), since
fixation and paraffin embedding change the wild-type speckled pattern
to a diffuse pattern.160,177 Immunocytochemistry is
especially useful in recognizing the microgranular variant of APL
(M3V) The (11;17) and (5;17) translocations.
In the rare t(11;17) and t(5;17) anomalies, the portion of RAR The (2;5)(p23;q35) translocation and its variants The NPM and ALK genes.
The (2;5)(p23;q35) translocation, which is associated with
ALCL,198-200 fuses the NPM gene, which encodes
the ubiquitously expressed nucleolar phosphoprotein NPM, on chromosome
5 to the ALK gene, which encodes a receptor tyrosine
kinase.201,202 The resulting NPM-ALK hybrid protein (also
known as p80) contains 40% of the amino-terminal portion of NPM linked
to the entire intracytoplasmic domain of ALK.203-206 Six
variant translocations in which ALK fuses to a partner other than NPM
have been identified in human tumors207-213 (Table
4), but the classic NPM-ALK anomaly
accounts for more than 80% of ALK fusion genes. The
ALK gene appears not to be transcribed in normal lymphoid
cells, but the promoter or promoters for NPM or other
partners are assumed to induce transcription of the ALK fusion genes in lymphoma cells.201 NPM-ALK kinase activity
is induced as a result of cross-linking by the NPM portion or one of
the other fusion partners. Initial estimates of the frequency of t(2;5)
and the resulting NPM-ALK gene in ALCL varied
widely,214-219 but most of this uncertainty has since been
resolved through immunocytochemical studies of ALK expression.
Antibodies to ALK. The laboratory that identified the p80 protein (later shown to be identical to NPM-ALK) prepared an affinity-purified polyclonal antibody to the kinase domain,220-222 and several immunocytochemical studies were conducted with samples made available to other researchers.218,219,223,224 A second polyclonal antibody (anti-ALK 11) has been used on a more limited scale for biochemical and immunocytochemical studies.225,226 However, most studies of ALK protein are now done with mAbs. Two such reagents have been described: ALK1 and ALKc. These recognize the cytoplasmic portion of ALK227,228 and are both suitable for immunolabeling paraffin-embedded biopsy specimens and for Western blot analyses.227-230 Antibodies to NPM. MAbs against the carboxy-terminal portion of NPM were described more than 15 years ago.231 More recently, 3 paraffin-reactive antibodies recognizing epitopes on the carboxy-terminal portion (which is lost in the NPM-ALK hybrid kinase) or the amino-terminal portion (present in NPM-ALK) have been raised.232 Expression of ALK and NPM in normal tissues and cell lines. ALK protein cannot be detected in tissues of human adults, except in a few cells in the nervous system that show weak labeling.227,228 RT-PCR has detected NPM-ALK and ATIC-ALK mRNA at low levels in normal and reactive lymphoid cells,233,234 but ALK-positive circulating cells cannot be detected by immunocytochemistry.227 Cell lines with t(2;5) are ALK positive, as are some neuroblastoma cell lines235 and the rhabdomyosarcoma line Rh30,227 all of which express full-length ALK protein.201,227 In contrast to ALK, NPM can be detected in most human cells by immunocytochemical techniques, usually confined to cell nuclei.232 Expression of ALK in lymphoid neoplasia.
The absence of ALK protein from normal lymphoid tissue means that
positive ALK staining is a near-specific marker for lymphomas containing a hybrid ALK gene (Figure
8). When a lymphoma expresses ALK, the
subcellular labeling pattern is informative (Table 4). Thus, in cases
with the classic t(2;5), ALK is observed not only in the cytoplasm but
also in the nucleus (Figure 8A), whereas tumors expressing ALK fusion
proteins other than NPM-ALK show no nuclear labeling because they do
not dimerize with wild-type NPM (Figure
8C).227,228,230,236,237 Furthermore, 2 ALK fusion proteins
(CTCL-ALK and moesin-ALK) were found to have unique immunohistochemical staining patterns (granular cytoplasmic and membrane-associated, respectively; Figure 8C).210,212 Staining for the
amino-terminal of NPM can also be informative because it is detected in
both the cytoplasm and the nucleus in tumor cells with
t(2;5),232 whereas staining in lymphomas with variant
translocations is restricted to the nucleus.238 Western
blotting of cryostat-section extracts can also be used to characterize
variant ALK proteins, whose molecular weights differ from that of
NPM-ALK.239
Extensive immunohistologic studies have shown that ALK-positive tumors correspond only partly to what pathologists diagnosed in the past as ALCL.217,219,223,227,228,237 ALK-positive lymphomas typically contain a population of medium to large hallmark neoplastic cells, with a reniform eccentric nucleus and a juxtanuclear hof in the Golgi region.222,230 However, the morphologic variation is wide228-230,240,241 and includes cases with a relatively uniform proliferation of hallmark cells,242 tumors in which many bizarre large cells (sometimes with a sarcomatoid appearance) are observed, and neoplasms containing large numbers of macrophages (the lymphohistiocytic pattern) or other reactive cells.11,243-245 ALK-positive lymphomas may contain areas of small cells that also express ALK protein.228,230 This indicates that the large cells do not represent cytologic transformation of a small cell tumor after acquisition of an ALK translocation. In cutaneous T-cell lymphoma, cellular transformation can create this mixed large and small cell pattern, but these cases are ALK negative and lack the NPM-ALK gene.246 When the small cell component is prominent,247 the tumor is sometimes referred to as the "small cell variant" of ALK-positive lymphoma.228,230,236,237 There is no reason, however, to think of this as a different disease, although spread of the disease to the peripheral blood and bone marrow may be more likely in cases of this sort.248,249 ALK-positive lymphomas usually express T-cell markers and/or cytotoxic granule proteins, CD30, and epithelial membrane antigen and c-Myc.219,222,228,230,250 Unlike ALK-negative cases, ALK-positive ALCLs are consistently BCL2 negative.58,59 We have found that tumors that are diagnosed morphologically as ALCL but have a B-cell phenotype are always ALK negative,228,251 and they probably represent one end of the morphologic spectrum of diffuse large B-cell neoplasia.11,251 Primary CD30-positive cutaneous lymphomas are also ALK negative, in keeping with the absence of the NPM-ALK gene.252 Finally, the controversial proposed "Hodgkin-like" subtype of ALCL11 is almost always ALK negative219,227,228,230 (as are Reed-Sternberg cells219,223,224,227,228) and probably represents true HD. Most important, lymphomas defined by ALK labeling appear to be clinically homogeneous, regardless of whether they have the classic t(2;5) or one of its variants. They are usually found in young men presenting with advanced disease (stage III-IV), are often associated with systemic symptoms (especially fever) and involvement of extranodal sites (especially skin, bone, and soft tissues), respond well to chemotherapy, and have a favorable outcome.221,237,253,254 Whether the high proliferative rate of the tumor,255 the host immune response to the ALK protein,256 or both these factors contribute to this pattern must be clarified in additional studies. In contrast, ALK-negative lymphomas with anaplastic large cell morphologic features tend to occur in older patients and usually have an unfavorable prognosis.221,253,254,257 Rare cases of ALK-positive large B-cell lymphoma have been described. These are characterized by immunoblastic (rather than anaplastic) morphologic features, expression of full-length ALK, and cytoplasmic IgA (Figure 8C).258 The ALK-positive lymphomas with a B-cell phenotype described by Gascoyne et al254 may belong to this rare category, but there is insufficient information to confirm this. ALK protein is not detectable in most nonhematopoietic neoplasms. The only exceptions are a few cases of rhabdomyosarcoma228 and neuroblastoma,235 both of which produce full-length ALK, possibly reflecting their primitive origin. In contrast, in the rare entity known as "inflammatory myofibroblastic tumor," ALK expression is commonly found and appears to reflect the presence of an ALK fusion protein (eg, TPM3-ALK, TPM4-ALK, or clathrin-ALK).208,259-261 Clinical applications of anti-ALK antibodies. Immunohistologic staining for ALK in lymphoid tissue biopsy specimens is now a widely used hematopathologic marker for diagnosing the clinicopathologic entity associated with t(2;5) and its variants, for which the name "ALK-positive lymphoma"228,230,236 seems most appropriate (rather than "ALCL"). ALK labeling can also be of value in discerning low levels of tumor tissue infiltration in such cases (eg, in bone marrow trephine specimens249,253) and identifying cases in which the neoplastic cells are obscured by macrophages.229 The small cell variant of ALK-positive lymphoma247 can also be distinguished, because of its positive labeling for ALK, from peripheral T-cell lymphomas.228 Moreover, inflammatory myofibroblastic tumors208 that express the ALK protein as a result of translocations involving the ALK gene can also be diagnosed by using ALK labeling, and the absence of CD30 distinguishes them from ALK-positive lymphomas. Other translocations.
Two translocations involving fusion of NPM with genes other
than ALK have been described, and both are rare. The
(5;17)(q32;q21) translocation in APL fuses the NPM gene to
the RAR
Studies of the proteins encoded by genes involved in chromosomal alterations in hematologic neoplasms have lagged behind molecular biologic investigations of these anomalies because of the investment of resources required to make satisfactory antibodies, a process that depends on the availability of antigen. It is sometimes possible to raise highly specific antibodies against synthetic peptides (eg, anti-BCL-27 and PML154), but the best immunogens are probably recombinant proteins, the production of which is not simple. Furthermore, although polyclonal reagents have been used for immunocytochemical studies and Western blotting analyses (in which nonspecific reactions can be to some extent ignored), they may introduce problems of nonspecific reactivity, variation between different samples, and limited availability. Therefore, mAbs are preferable, but reagents that satisfy stringent criteria for specificity are not easy to produce. Antibodies should detect fixation-resistant epitopes in paraffin-embedded tissue, but those that meet this requirement are more difficult to produce. Despite these problems, specific antibodies to the products of genes involved in hematologic neoplasia have provided major new insights, particularly when the protein target is relevant not only to hematologic neoplasia specifically but also to cell physiology in general. The best of example of this is BCL-2, a protein that was first studied in lymphomas with the t(14;18) but that subsequently was found to be extremely important in apoptosis. Most antibodies discussed here can detect their targets through biochemical methods (Western blotting or immunoprecipitation). These techniques are particularly applicable to the study of hybrid genes, since they allow chimeric proteins (eg, the products of the hybrid BCR-ABL and NPM-ALK genes239,263,264) to be distinguished from wild-type proteins on the basis of their unique molecular sizes. Biochemical analysis can also be useful when a gene (eg, AML1265) encodes several transcripts. However, compared with immunocytochemistry, biochemical methods are more demanding technically and provide only limited information on tissue distribution and subcellular localization of the proteins. Immunocytochemistry thus has obvious advantages for studying tissue distribution and localization. We have here discussed genetic anomalies that switch on quiescent genes separately from those that create fusion genes. For the anomalies that switch on genes, a major consideration is the expression pattern of the gene product in normal cells. Immunocytochemical studies of widely expressed genes (eg, c-MYC) generally have little clinical value. In contrast, few normal cells express the products of the BCL-1 and TAL-1 genes, and immunocytochemical staining for these proteins has a role in the diagnosis of mantle cell lymphoma and T-ALL, respectively. Molecules such as BCL-2 and BCL-6 are in an intermediate position: both are expressed by many cells in the absence of gene rearrangement, but immunocytochemical labeling can be useful in certain situations. For example, BCL-2 is a good marker for the t(14;18) if normal germinal-center B cells, which are consistently BCL-2 negative, are compared with their neoplastic counterparts, follicular lymphoma cells, which are usually BCL-2 positive. Thus, immunocytochemical detection of BCL-2 protein has a diagnostic role in distinguishing between reactive and neoplastic follicle centers, even though it is widely expressed outside the germinal center. BCL-6 is not a comparably specific immunocytochemical marker for gene translocation (even in a restricted context), but it has diagnostic value as a molecule associated with germinal-center cells. Antibodies to chimeric proteins generated by fusion genes are
theoretically less suitable for immunocytochemical analyses, since they
are usually raised against one of the 2 constituent proteins and
therefore react with both wild-type and hybrid proteins. Antibodies
specific for junctional epitopes unique to the chimeric protein should
avoid this problem, but despite reports of such epitopes on the
BCR-ABL,266,267 AML1-ETO,265 and
E2A-PBX1268 chimeric proteins Therefore, although in theory it should be possible to produce antibodies specific for hybrid proteins, in practice such antibodies remain elusive. If short recombinant protein sequences (or synthetic peptides) are used as immunogens, the junctional region may not adopt the same 3-dimensional conformation that it has in the chimeric protein in vivo. Furthermore, the junctional sequences may not be immunogenic, an issue that has been addressed, at least with respect to T-cell recognition, in several studies. For example, there is evidence that junctional BCR-ABL peptides can be bound by HLA class I molecules,269,270 and several investigators271 have reported that in vitro immunization with a peptide from p210 BCR-ABL can elicit a specific cytotoxic response. However, it is not yet clear whether the BCR-ABL junctional sequence is immunogenic in vivo.272 Peptides eluted from HLA molecules on fresh chronic myeloid leukemia cells include those from the BCR protein but not junctional sequences.273 Antibodies specific for chimeric oncogene products will therefore
always be difficult, if not impossible, to produce. However, the 2 examples discussed here (PML-RAR Immunocytochemical labeling for the NPM-ALK chimeric protein
illustrates a point of wider relevance: the importance of subcellular localization patterns. Several proteins move from the cytoplasm to the
nucleus under physiologic conditions. For example, the dimeric p50/p65
nuclear factor-
Another leukemia-associated protein that relocates to a site that may
not be relevant to its action is PML, which is displaced in APL cells
from its normal target sites (ie, nuclear bodies) through
heterodimerization with the PML-RAR In conclusion, antibodies specific for the products of genes involved
in chromosomal changes in leukemia and lymphoma have proved to be
valuable both for studying normal cell physiology (eg, BCL-2) and for
diagnosis (eg, BCL-1, PML, and NPM-ALK). The scope of antibody-based
studies should continue to expand as new genetic changes in lymphoma
and leukemia are identified.279 Furthermore, microarray
studies of the expression of large numbers of gene sequences are likely
to reveal new potential immunocytochemical markers of clinical
relevance associated with subtypes of disease280-282 or
prognosis.280 However, researchers choosing candidate
proteins against which to raise antibodies must recognize that the
level of mRNA extracted from a cell suspension (and particularly from a
biopsy specimen) does not necessarily correlate with the level of the
corresponding protein in the tumor cells. This consideration is
relevant to a microarray study of human B-cell
lymphoma.282 Figure 9 shows
the mRNA expression data from this study for protein markers previously
investigated immunohistologically in DLCL. The mRNA patterns for
purified cells appear to correlate with protein expression (eg, the
absence of B-cell gene expression in T cells and the expression of CD10
and BCL-2 in purified germinal-center cells). However, expression of
the proteins studied is known to range in DLCL from less than 40% of
cases (CD10) to essentially all cases (class II, CD20, and CD79), and
these documented differences in protein expression are not, at least on
first inspection, reflected in the mRNA profiles for the corresponding
genes, which show little obvious differences.
Thus, the process of translating new molecular biologic findings into practical antibody-based techniques for assessing human tumor samples will continue to require a combination of judicious discrimination in choosing clinically important molecules and skill in making and characterizing specific antibodies. Given the large number of genes from which to choose the right candidates and the lotterylike nature of mAb production, an element of luck would also help!
This article is dedicated to the memory of Carlo Falini. The authors also wish to express their gratitude to their collaborators who have contributed with great skill over the years to the production and characterization of many of the reagents referred to in this review.
Submitted April 2, 2001; accepted September 21, 2001.
Supported by Associazione Italiana per la Ricerca sul Cancro (B.F.) and the Leukaemia Research Fund of Great Britain (D.Y.M.).
The authors contributed equally to this work.
Reprints: Brunangelo Falini, Istituto di Ematologia, Policlinico, Monteluce, 06100 Perugia, Italy.
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Top
Abstract
Introduction
is highly distinctive. Similarly, antibodies to the
anaplastic lymphoma kinase (ALK) tyrosine kinase are valuable (because
wild-type ALK is not found in normal lymphoid tissue) in detecting
neoplasms (CD30-positive large T-cell lymphomas) with t(2;5) or its
variants. Thus, immunocytochemical detection of the products of many
rearranged genes in lymphoma and leukemia can be clinically informative
and provide information on cellular and subcellular protein expression that cannot be inferred from studies based on messenger RNA.
(Blood. 2002;99:409-426)
locus.
which is characterized by sparse cytoplasmic granules and marked
nuclear irregularity, with folding, lobulation, or convolution
transcription factor is normally held in the
cytoplasm by the inhibitor protein I