Genetic Relatedness of Lymphoid Malignancies: Transformation of Chronic Lymphocytic Leukemia as a Model

  1. Kenneth A. Foon, MD;
  2. Raghu Thiruvengadam, MD;
  3. Alan Saven, MD;
  4. Zale P. Bernstein, MD; and
  5. Robert Peter Gale, MD, PhD
  1. From the Markey Cancer Center and the Division of Hematology and Oncology, Department of Medicine, University of Kentucky, Lexington, Kentucky; Scripps Clinic and Research Foundation, La Jolla, California; Roswell Park Cancer Institute, Buffalo, New York; University of California at Los Angeles, Los Angeles, California. Requests for Reprints: Kenneth A. Foon, MD, Markey Cancer Center, 800 Rose Street, Room 140, Lexington, KY 40536-0093. Acknowledgments: The authors thank Drs. John Spinosa and Douglas Ellison for histopathologic materials, Dr. Richard McPherson for the Southern blot, and Dr. Ann Marie Block for the karyotype.
     
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    Abstract

    Objective: Studies concerning the genetic relatedness between chronic lymphocytic leukemia and the more aggressive B-cell cancers that develop in about 10% of affected persons were reviewed. These B-cell cancers include large B-cell lymphoma (the Richter syndrome), prolymphocytic transformation, acute lymphoblastic leukemia, and multiple myeloma. Two possible relations were evaluated: development from the chronic lymphocytic leukemia clone (clonal evolution) and development of a genetically unrelated, independent second cancer.

    Data Analysis: Analysis of genetic relatedness between the two cancers considered concordance for immunoglobulin gene rearrangements, for immunoglobulin isotypes and idiotypes, and for cytogenetic abnormalities.

    Conclusions: In the case of large B-cell lymphoma, generally thought to arise from the chronic lymphocytic leukemia clone, approximately one half of the patients had genetically unrelated cancers. In prolymphocytic transformation, all cases studied appeared to evolve from the chronic lymphocytic leukemia clone. The few studies of acute lymphoblastic leukemia and multiple myeloma showed genetic relatedness in some cases and unrelatedness in others. These data indicate that progression to more aggressive B-cell cancers in persons with chronic lymphocytic leukemia can result from either clonal evolution or from an independent transforming event.

    Chronic lymphocytic leukemia is a clonal proliferation of a subset of B cells that express the CD5 antigen and that are probably involved in some aspects of autoimmunity [1]. Because chronic lymphocytic leukemia develops from one transformed B cell, all the leukemia cells contain identically rearranged immunoglobulin heavy- and light-chain genes and produce identical immunoglobulin molecules with the same isotype and idiotype.

    Data Sources: An English-language medical literature search was done using MEDLINE (1982 to 1992) and CANCERLIT (1982 to 1992). An extensive manual search of the literature that included meeting abstracts and reports was also done. Approximately 500 articles, abstracts, and book chapters were identified; 102 were selected for detailed analysis.

    Although chronic lymphocytic leukemia is typically stable over several years, progression to more aggressive B-cell cancers occurs in about 10% of persons at risk. These more aggressive B-cell cancers include large B-cell lymphoma (the Richter syndrome), prolymphocytic transformation, acute lymphoblastic leukemia, and multiple myeloma (Figure 1). The relation between these disorders and chronic lymphocytic leukemia is unclear and controversial. Some data suggest that these cancers are genetically related to the chronic lymphocytic leukemia clone. Other data suggest that they are genetically unrelated to the chronic lymphocytic leukemia clone. We evaluated studies designed to analyze whether progression of chronic lymphocytic leukemia to more aggressive B-cell cancers results from clonal evolution or from the development of an independent genetically unrelated cancer.

    Figure 1. Transformation of one B cell to produce chronic lymphocytic leukemia is shown. Clonality is confirmed by analysis of immunoglobulin genes (Southern blotting), antibodies (anti-isotypic and anti-idiotypic), or chromosome analysis. The karyotype in the Figure shows a trisomy 12, and the Southern blot shows the same germline in the normal ( ) and the patient's ( ) peripheral blood cells (bar). A single immunoglobulin gene rearrangement is identified in the patient's cells () but not in the normal cells. Anti-idiotype antibodies are depicted as red with a green fluorescein tag and show specific reactivity with the immunoglobulin on the chronic lymphocytic leukemia cells. Determining genetic relatedness of the chronic lymphocytic leukemia clone to large B-cell lymphoma, prolymphocytic transformation, acute lymphoblastic leukemia, or multiple myeloma requires reactivity with the same anti-idiotype antibody, showing identical immunoglobulin gene rearrangements or identical karyotype.
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      Figure 1. Transformation of one B cell to produce chronic lymphocytic leukemia is shown. Clonality is confirmed by analysis of immunoglobulin genes (Southern blotting), antibodies (anti-isotypic and anti-idiotypic), or chromosome analysis. The karyotype in the Figure shows a trisomy 12, and the Southern blot shows the same germline in the normal ( ) and the patient's ( ) peripheral blood cells (bar). A single immunoglobulin gene rearrangement is identified in the patient's cells () but not in the normal cells. Anti-idiotype antibodies are depicted as red with a green fluorescein tag and show specific reactivity with the immunoglobulin on the chronic lymphocytic leukemia cells. Determining genetic relatedness of the chronic lymphocytic leukemia clone to large B-cell lymphoma, prolymphocytic transformation, acute lymphoblastic leukemia, or multiple myeloma requires reactivity with the same anti-idiotype antibody, showing identical immunoglobulin gene rearrangements or identical karyotype. Scheme of development of chronic lymphocytic leukemia.leftright
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      Data Sources

      An English-language medical literature search was conducted using MEDLINE (1982 to 1992) and CANCERLIT (1982 to 1992). An extensive manual search of the literature that included meeting abstracts and reports was also done. Approximately 500 articles, abstracts, and book chapters were identified, 102 of which were selected for detailed analysis.

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      Techniques To Determine Genetic Relatedness between B-Cell Cancers

      In chronic lymphocytic leukemia, in which the expansion is clonal, investigators have tried to determine genetic relatedness between the original leukemia and subsequent, more aggressive B-cell cancers.

      The strategy to determine genetic relatedness between B-cell cancers involves analyzing immunoglobulin genes and their productsantibodies. We discuss these topics sequentially, moving from the structure of immunoglobulin genes to antibody isotypes and idiotypes. Last, we discuss the use of cytogenetic analysis.

      Immunoglobulin Gene Rearrangements

      In immature B cells, immunoglobulin heavy- and light-chain genes are unrearranged or in germline configuration. As B cells mature, these genes must undergo rearrangement to allow them to encode for immunoglobulin molecules [2-4]. Immunoglobulin gene rearrangement is complex. The DNA sequences that are physically separated in the germline configuration of the gene are juxtaposed by deleting intervening genetic material. Heavy-chain gene rearrangement is the first step. Each B cell has two heavy-chain alleles. Each allele may be successfully rearranged or deleted. If the attempt to rearrange the first heavy-chain allele is unsuccessful, the cell attempts to rearrange the second heavy-chain allele. Only if this attempt is successful does the cell proceed to light-chain rearrangement. Rearrangement of light-chain genes is similar, proceeding, if necessary, through both alleles followed by both alleles.

      Rearrangement of immunoglobulin genes can be identified by Southern blotting (Figure 2). Here, cellular DNA is cut with restriction endonucleases and is electrophoresed to separate molecules of different sizes. Those DNA molecules containing sequences that encode immunoglobulin genes are identified by hybridization to radiolabeled probes homologous to one or more constant regions. Experimental conditions are such that radiolabeled bands are detected only when clonal immunoglobulin gene rearrangement is present.

      Figure 2. High-molecular-weight DNA is isolated from fresh, frozen, or fixed tissues; digested with restriction endonuclease enzymes; and electrophoresed overnight in agarose gel to separate DNA fragments of different sizes. These fragments are then transferred to nitrocellulose filters by Southern blotting and the filters are hybridized with Phosphorus-32-labeled DNA probes homologous to immunoglobulin heavy- and light-chain constant region genes. Autoradiography is then done. Labeled bands are detected on roentgenographic films only when clonal immunoglobulin gene rearrangement is present. The Southern blot shown is an EcoRI restriction enzyme. The normal (N) column shows a germline (bar), and the patient's (P) column also shows a gene rearrangement ( ) in addition to the germline.
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        Figure 2. High-molecular-weight DNA is isolated from fresh, frozen, or fixed tissues; digested with restriction endonuclease enzymes; and electrophoresed overnight in agarose gel to separate DNA fragments of different sizes. These fragments are then transferred to nitrocellulose filters by Southern blotting and the filters are hybridized with Phosphorus-32-labeled DNA probes homologous to immunoglobulin heavy- and light-chain constant region genes. Autoradiography is then done. Labeled bands are detected on roentgenographic films only when clonal immunoglobulin gene rearrangement is present. The Southern blot shown is an EcoRI restriction enzyme. The normal (N) column shows a germline (bar), and the patient's (P) column also shows a gene rearrangement ( ) in addition to the germline. Southern blotting.arrows

        Although this approach detects clonal immunoglobulin gene rearrangement in most cases, it has some limitations. First, no band may be detected if the clonal population is fewer than 5% of the cells being tested. Second, certain situations might alter the Southern blot pattern, even when clonal malignancy exists. For example, somatic mutations that cause single base-pair substitutions in the variable region at a restriction-enzyme cleavage site could alter the pattern of bands [5]. Imprecise joining of immunoglobulin gene segments and random nucleotide insertion during recombination of the variable gene subsegments can alter the pattern of bands detected by Southern blot [6, 7]. Finally, multiple patterns of gene rearrangement could be generated from an uncommitted precursor with a partially or incompletely rearranged immunoglobulin gene.

        Immunoglobulin Isotypes

        Another technique to determine the genetic relatedness between B-cell cancers involves analysis of the concordance for immunoglobulin heavy- or light-chain isotypes on the B-cell surface (surface membrane immunoglobulin), in the B-cell cytoplasm (cytoplasmic immunoglobulin), or on immunoglobulin molecules (or light chains) secreted into the blood or urine (monoclonal or M component).

        Studies of immunoglobulin isotypes are usually done by staining fresh or fixed B cells with antibodies specific for different immunoglobulin classes such as , , or heavy chains or or light chains. Detection of labeled cells is facilitated using a second antibody labeled with fluorescein or linked to an indicator system such as peroxidase and its substrate or biotin-avidin. Immunoglobulins in serum and urine specimens are usually analyzed by immune precipitation, diffusion, or electrophoresis with similar immunoglobulin class-specific antibodies.

        When two B-cell cancers express the same immunoglobulin isotypes by these techniques, they may be are considered to be genetically related, whereas those that are discordant for immunoglobulin isotypes are considered to be genetically unrelated. Genetic relatedness in this setting is generally interpreted as an indication of clonal evolution, whereas genetic unrelatedness is interpreted as an indication of a cancer with a separate cell of origin.

        Several issues complicate the use of this approach to determine genetic relatedness of B-cell cancers. First, concordance of immunoglobulin heavy- and light-chain isotypes is consistent with, but does not prove, genetic relatedness. For example, two genetically unrelated B-cell cancers have a 50% or greater chance of having the same immunoglobulin light-chain isotype ( or ). The likelihood of chance concordance is even greater because of selective use of immunoglobulin heavy- and light-chain genes in B-cell cancers including chronic lymphocytic leukemia [1]. Second, immunoglobulin heavy- or light-chain isotypes can be discordant, even in B-cell cancers that are genetically related. This discordance occurs as a result of isotype switching, such as that from to heavy chain, or from to light chain, a process that is well recognized during normal B-cell ontogeny [8-10]. Whether the frequency of isotype switching is higher in malignant compared with normal B cells is unknown. A third limitation arises when two B-cell cancers develop in parallel from a transformed immature B cell with germline or incompletely rearranged immunoglobulin heavy- or light-chain genes. Here the two cancers, although genetically related, can show completely different heavy- or light-chain isotypes [11].

        These considerations suggest that, although comparison of immunoglobulin heavy- and light-chain isotypes is of interest, several factors limit the accuracy of this approach in defining genetic relatedness between B-cell cancers.

        Immunoglobulin Idiotypes

        Immunoglobulin molecules share many common structural features. Identification of immunoglobulin isotypes, as we described, uses reagents that identify these shared features such as the common regions of the heavy and light chains on the Fc portion of the molecule. However, immunoglobulins also contain unique structural features such as the antibody-binding site on the Fab portion of the molecule. Considerably more variability exists in the amino acid sequence of the antibody-binding site than in the common regions of immunoglobulins.

        The variability of the amino acid sequence of the antibody-binding region is concentrated in three hypervariable regions called complementarity-determining regions (CDRs) that bind directly to the antigen. Antibodies generated to the CDRs of an immunoglobulin molecule are called anti-idiotype antibodies. The specific CDRs they identify are called the idiotype. In the case of B-cell malignancies, these anti-idiotype antibodies can be used to fingerprint a clone of malignant cells and differentiate them from normal B cells and other B-cell cancers. Although this approach is more specific than immunoglobulin isotyping Figure 3, one complicating factor is the reported somatic mutation in the active immunoglobulin gene [11-14]. Although the cells express the same isotype and even a single immunoglobulin gene rearrangement, the idiotype is altered. Such hypermutation of immunoglobulin genes is commonly reported in follicular lymphoma but is rare in chronic lymphocytic leukemia.

        Figure 3. Immunoglobulin is isolated from a human B-cell tumor by fusing it with immunoglobulin nonsecreting murine myeloma cells using polyethylene glycol (PEG). The immunoglobulin is purified, mixed with complete Freund adjuvant (CFA), and used to immunize BALB/c mice. Immunized mice are killed, and B cells from the spleen are fused with immunoglobulin nonsecreting murine myeloma cells. Supernatants from the hybridomas are tested for anti-idiotype antibodies by screening for reactivity against immunoglobulin from the original human B-cell tumor. Supernatants with antibodies reacting only with the immunoglobulin from the original B-cell tumor are identified, subcloned, and retested for specific anti-idiotype reactivity. After anti-idiotype antibodies are identified, they can be used to identify B cells by flow cytometric or immunochemical techniques. With rare exceptions, they react specifically with the original B-cell tumor cells and not with normal B cells or other B-cell tumors.
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          Figure 3. Immunoglobulin is isolated from a human B-cell tumor by fusing it with immunoglobulin nonsecreting murine myeloma cells using polyethylene glycol (PEG). The immunoglobulin is purified, mixed with complete Freund adjuvant (CFA), and used to immunize BALB/c mice. Immunized mice are killed, and B cells from the spleen are fused with immunoglobulin nonsecreting murine myeloma cells. Supernatants from the hybridomas are tested for anti-idiotype antibodies by screening for reactivity against immunoglobulin from the original human B-cell tumor. Supernatants with antibodies reacting only with the immunoglobulin from the original B-cell tumor are identified, subcloned, and retested for specific anti-idiotype reactivity. After anti-idiotype antibodies are identified, they can be used to identify B cells by flow cytometric or immunochemical techniques. With rare exceptions, they react specifically with the original B-cell tumor cells and not with normal B cells or other B-cell tumors. Generation of anti-idiotype antibodies.

          Cytogenetics

          An alternative approach to determining genetic relatedness between B-cell cancers is cytogenetic analysis. Concordance for cytogenetic abnormalities is usually interpreted as an indication of genetic relatedness, whereas discordance is thought to be an indication of genetic unrelatedness (Figure 4). Recent studies using B-cell mitogens have shown different rates and types of cytogenetic abnormalities in different B-cell cancers. In chronic lymphocytic leukemia, cytogenetic abnormalities are reported in about 50% of cases [15-17]. The most common abnormality is trisomy 12. Others include rearrangements involving chromosomes 11q, 13q, and 14q+. Except for rearrangement of chromosome 14q+, which is commonly found in patients with B-cell prolymphocytic leukemia [18], chromosomal abnormalities typical of chronic lymphocytic leukemia are uncommon in large B-cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma. Consequently, detection of trisomy 12, 11q+, or 13q+ in chronic lymphocytic leukemic cells and the more aggressive B-cell cancer strongly supports genetic relatedness.

          Figure 4. Cells from blood, bone marrow, or lymph nodes are stimulated to divide using B-cell mitogens such as lipopolysaccharide, Epstein-Barr virus, staphylococcus protein A, or pokeweed mitogen. Three to 5 days later, the cells are treated with Colcemid to block cell division in metaphase, and the cells are recovered for analysis. Cells are treated with hypotonic solution to disrupt the nuclear membrane and then fixed in methanol and acetic acid, centrifuged, resuspended in fixative, and placed onto slides. Slides are stained with Giemsa or quinacrine to identify chromosome bands and are then photographed. Twenty-six metaphases are typically analyzed. Arrow denotes the extra chromosome 12.
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            Figure 4. Cells from blood, bone marrow, or lymph nodes are stimulated to divide using B-cell mitogens such as lipopolysaccharide, Epstein-Barr virus, staphylococcus protein A, or pokeweed mitogen. Three to 5 days later, the cells are treated with Colcemid to block cell division in metaphase, and the cells are recovered for analysis. Cells are treated with hypotonic solution to disrupt the nuclear membrane and then fixed in methanol and acetic acid, centrifuged, resuspended in fixative, and placed onto slides. Slides are stained with Giemsa or quinacrine to identify chromosome bands and are then photographed. Twenty-six metaphases are typically analyzed. Arrow denotes the extra chromosome 12. Cytogenetic analysis.

            Genetically related tumors may have identical karyotypes (as described above), may share some cytogenetic abnormalities, and, theoretically, may even have different abnormalities. An example of shared abnormalities is evolution of chronic myelogenous leukemia from the chronic to the acute (blast) phase. Cells from both phases have a common chromosomal abnormality: the t(9; 22) translocation responsible for producing the Philadelphia chromosome. Acute-phase cells often contain additional cytogenetic abnormalities. The presence of the t(9; 22) translocation in both disease phases, however, confirms their genetic relatedness. Similar findings are reported in B-cell malignancies [19-21]. Finally, genetically related tumors may have different chromosome abnormalities. Although we assume that tumors with differing chromosomal abnormalities are genetically unrelated, a theoretical basis to this event does exist. One possibility is that the transforming event occurs before the chromosomal changes in a very primitive cell. It is conceivable, then, that two different progeny of this primitive cell might undergo different chromosomal changes.

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            Results

            Large B-Cell Lymphoma (the Richter Syndrome)

            In 1928, Maurice Richter described a patient with chronic lymphocytic leukemia and reticulum cell sarcoma [22]. He was unable to establish the relations between these entities and concluded that There is no evidence of the transformation of the cells of one lesion into those of the other. Lymphocytes and tumor cells, although intimately intermingled, are morphologically distinct . The evidence presented by the microscopic preparations thus enables one only to diagnose the presence of two lesions, without giving any definitive indication that they are genetically related.

            Of persons with chronic lymphocytic leukemia, 5% to 10% progress to a large B-cell lymphoma (the modern equivalent of reticulum cell sarcoma) Figure 5 [23-25]. Similar progression to large B-cell lymphoma occurs in diffuse, small B-cell lymphoma (the lymphoma counterpart of chronic lymphocytic leukemia [26]) and in Waldenstrom macroglobulinemia, a related disorder. Occasional cases of Hodgkin disease [26-29] and malignant histiocytosis [30] have also been reported in persons with chronic lymphocytic leukemia.

            Figure 5. Low-power magnification of lymph node showing small-cell infiltration on the left and large cells on the right (hematoxylin and eosin; magnification 500). High-power magnification of the same lymph node showing small cells on the left and large cells on the right (magnification, 2500). Low-power magnification of bone marrow from the same patient showing small and large cells (hematoxylin and eosin; magnification, 500). High-power magnification of bone marrow showing predominantly small cells on the left and large cells on the right (hematoxylin and eosin; magnification, 2500).
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              Figure 5. Low-power magnification of lymph node showing small-cell infiltration on the left and large cells on the right (hematoxylin and eosin; magnification 500). High-power magnification of the same lymph node showing small cells on the left and large cells on the right (magnification, 2500). Low-power magnification of bone marrow from the same patient showing small and large cells (hematoxylin and eosin; magnification, 500). High-power magnification of bone marrow showing predominantly small cells on the left and large cells on the right (hematoxylin and eosin; magnification, 2500). Lymph node and bone marrow from a patient with chronic lymphocytic leukemia evolving to large B-cell lymphoma.Top left.Top right.Bottom left.Bottom right.

              Persons in whom chronic lymphocytic leukemia progresses to large B-cell lymphoma typically develop fever, abdominal pain, weight loss, and progressive lymphadenopathy (often in one lymph node site), hepatomegaly and splenomegaly, and decreased hemoglobin and platelet counts [23, 24, 31] (Table 1). Unusual extranodal sites of disease may include the brain, respiratory tract, skin, and gastrointestinal tract [32-37].

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              Table 1. Clinical Features of Large B-Cell Lymphoma in Patients with Chronic Lymphocytic Leukemia*

              The risk for progression to large B-cell lymphoma appears to be independent of previous therapy for chronic lymphocytic leukemia. In one study, persons with chronic lymphocytic leukemia and complex chromosome abnormalities (with or without trisomy 12) were more likely to progress to large B-cell lymphoma than were those without this feature [38]. Although most cases of large B-cell lymphoma in persons with chronic lymphocytic leukemia develop after several years, synchronous presentations have been reported. The outcome of persons with chronic lymphocytic leukemia and large B-cell lymphoma is poor, with a median survival time of about 4 months [23, 31].

              The relation between chronic lymphocytic leukemia and large B-cell lymphoma is controversial. Genetic relatedness was studied using anti-idiotype antibodies and immunoglobulin gene rearrangements (Table 2). In seven patients, identical immunoglobulin heavy-chain rearrangements were reported [37, 39-44]. Two of seven patients also had identical immunoglobulin idiotypes [39, 43]. In another person, cytogenetic analyses showed identical chromosome abnormalities in both cell types [45]. Five other patients showed different immunoglobulin heavy-chain rearrangements in chronic lymphocytic leukemia and large B-cell lymphoma cells [46-50]. Another patient showed different immunoglobulin heavy-chain rearrangement but identical immunoglobulin light-chain rearrangement [51]. This unusual finding suggests a deletion or point mutation in the immunoglobulin heavy-chain locus within the large B-cell lymphoma clone [12, 14, 52-54]. In another unusual case [40], chronic lymphocytic leukemia and large B-cell lymphoma cells had identical immunoglobulin heavy-chain rearrangements, but the light chain was in leukemia cells and in lymphoma cells. This finding contrasts with the usual hierarchy of isotype switching from to . Several possible explanations exist for this finding. One is that the large B-cell lymphoma evolved from the chronic lymphocytic leukemia clone when the latter was expressing light chains and that isotype switching later occurred in leukemia but not in lymphoma cells. A second possibility is that both the leukemia and lymphoma developed in parallel from a transformed immature B cell with rearranged immunoglobulin heavy-chain genes but germline light-chain genes. A similar explanation is offered for some complex cases of follicular B-cell lymphomas [12]. This concept of parallel rather than sequential development from a transformed B-cell progenitor may apply to other cases of concordance for chronic lymphocytic leukemia and large B-cell lymphoma.

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              Table 2. Chronic Lymphocytic Leukemia and Large B-Cell Lymphoma*

              Large B-cell lymphomas are also reported in severe combined immunodeficiency disease, persons with the acquired immunodeficiency syndrome (AIDS), and in transplant recipients receiving immunosuppressive drugs [55-57]. Persons with AIDS and chronic lymphocytic leukemia share similar immune abnormalities [1, 58], including decreased CD4 T cells (helper T cells), defective T-cell proliferation, decreased T-cell help for B-cell proliferation, and decreased natural killer cell and lymphokine-activated killer cell activities. Large B-cell lymphomas in both diseases are usually very aggressive, presumably because of impaired host immunity.

              Prolymphocytic Transformation

              Prolymphocytic transformation of chronic lymphocytic leukemia is characterized by a gradual increase in the fraction of leukemia cells resembling prolymphocytes. These large cells have abundant cytoplasm, open nuclear chromatin, and a prominent nucleolus (Figure 6). The prolymphocytes, like the chronic lymphocytic leukemia cells, express CD5 and have minimal expression of surface membrane immunoglobulin [59]. Some reports suggest that the prolymphocytes have increased surface membrane immunoglobulin [60-62]. We studied 10 patients with prolymphocytic transformation for genetic relatedness of these cells with the chronic lymphocytic leukemia cells. In addition to the presence of the CD5 antigen and low-intensity immunoglobulin, we found identical immunoglobulin surface isotypes and gene rearrangements in both [59]. These data suggest that prolymphocytic transformation usually evolves from the chronic lymphocytic leukemia clone. In contrast to the transformation to large B-cell lymphoma, prolymphocytic transformation of chronic lymphocytic leukemia has a modest, if any, effect on survival [60, 63]. Most data suggest that prolymphocytes are activated chronic lymphocytic leukemia cells [64]. This finding is consistent with in vitro studies in which cultured chronic lymphocytic leukemia cells sometimes acquire prolymphocyte features [64].

              Figure 6. (Wright stain; magnification, 2500.).
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                Figure 6. (Wright stain; magnification, 2500.). Blood from a patient with prolymphocytic transformation showing small chronic lymphocytic leukemia cells and large prolymphocytes with nucleoli.

                Prolymphocytic transformation of chronic lymphocytic leukemia should be distinguished from de novo prolymphocytic leukemia. The latter is a distinct entity unassociated with chronic lymphocytic leukemia [65, 66]. De novo prolymphocytic leukemia cells do not typically express CD5 and have intense surface membrane immunoglobulin expression [63], whereas prolymphocytic transformation of chronic lymphocytic leukemia cells express CD5 and have low-intensity surface membrane immunoglobulin identical to that of chronic lymphocytic leukemia cells. Clinically, persons with de novo prolymphocytic leukemia typically have very high white cell counts (> 150 109/L), composed predominantly of prolymphocytes, whereas the prolymphocytic transformation of chronic lymphocytic leukemia is characterized by a dual population of cells. Persons with de novo prolymphocytic leukemia typically have no lymphadenopathy, have massive splenomegaly, and usually require aggressive treatment.

                Acute Lymphoblastic Leukemia

                Transformation to acute lymphoblastic leukemia is rare in persons with chronic lymphocytic leukemia. In a review of 31 cases of acute leukemia developing in persons with chronic lymphocytic leukemia, only 10 were lymphoblastic [67]. In two cases of acute lymphoblastic leukemia and chronic lymphocytic leukemia, the presentation was synchronous. Similar immunoglobulin heavy- and light-chain isotypes were noted in five cases of acute lymphoblastic leukemia developing in persons with chronic lymphocytic leukemia [68-72]. In one of these cases, both immunoglobulins had rheumatoid factor activity. Identical cytogenetic abnormalities were reported in another case [73]. These data suggest that, in rare cases of chronic lymphocytic leukemia, evolution to acute lymphoblastic leukemia may occur; however, more definitive data are needed. Interestingly, this situation contrasts with chronic myelogenous leukemia, in which all cases progress to acute leukemia. Here, evolution is always from the chronic myelogenous leukemia clone.

                Multiple Myeloma

                Although the general notion is that chronic lymphocytic leukemia cells are frozen at an immature stage of B-cell development, this notion is probably incorrect. For example, small numbers of plasma cells express the same immunoglobulin idiotype as the chronic lymphocytic leukemia cells, suggesting that they originate from the leukemia clone [74]. Also, in vitro incubation of chronic lymphocytic leukemia cells with phorbol esters or B-cell mitogens induces differentiation to immunoglobulin-secreting plasma cells [75-78]. Mitogen-induced switching from cell-surface IgM to secreted IgG has also been reported [79]. These changes are associated with the appearance of an endoplasmic reticulum and other morphologic features typical of mature plasma cells. Immunoglobulin secretion is preceded by a rapid increase in mRNA coding for the secretory form of IgM [80], similar to normal plasma cells.

                Multiple myeloma is a rare complication of chronic lymphocytic leukemia. Only eight cases have been studied in detail (Table 3). In one case, immunoglobulin heavy-chain gene rearrangements were identical in the plasma cells and chronic lymphocytic leukemia cells; however, light-chain gene rearrangement was noted in the chronic lymphocytic leukemia cells compared with light-chain gene rearrangement in the plasma cells [81]. We discussed the possible basis for this finding in the section on large B-cell lymphoma, suggesting parallel development from a common transformed immature B cell. A second case showed different immunoglobulin heavy- and light-chain gene rearrangements [82]. A third case had IgG on the chronic lymphocytic leukemia cells and IgA on the plasma cells. Interestingly, these immunoglobulins had identical idiotypes, suggesting isotype switching [83]. This possibility was supported by in vitro studies. In a fourth study, four patients with multiple myeloma and chronic lymphocytic leukemia had the same immunoglobulin light-chain type, but two had different idiotypes [84] (data not shown). In another case, identical cytogenetic abnormalities were detected in the chronic lymphocytic leukemia and plasma cells [85]. Results of other studies [86-90] are summarized in Table 3.

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                Table 3. Chronic Lymphocytic Leukemia and Multiple Myeloma*

                These data suggest that, in at least some persons with chronic lymphocytic leukemia in whom multiple myeloma develops, the plasma cells evolve from the chronic lymphocytic leukemia clone. In other cases, genetic relatedness is less certain.

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                Conclusions

                Our data indicate two pathways for the development of more aggressive B-cell cancers in persons with chronic lymphocytic leukemia. Some cases are marked by evolution of the chronic lymphocytic leukemia clone. In other instances, a B-cell tumor develops that is genetically unrelated to the leukemia clone.

                These data raise several interesting issues. For example, why should persons with chronic lymphocytic leukemia be at such high risk for other B-cell cancers? We found an approximate 10% risk for progression of chronic lymphocytic leukemia. Even if only one half of these cases were genetically unrelated to chronic lymphocytic leukemia, the risk for B-cell cancer development would be about 10 times higher than that in the normal age-adjusted population.

                One explanation is that treatment of chronic lymphocytic leukemia causes these more aggressive B-cell cancers. This explanation is unlikely because alkylating drugs typically used to treat chronic lymphocytic leukemia are reported to increase the risk of acute myelogenous leukemia [91-94] but not of lymphoid cancers.

                Another theory is that the immunodeficiency associated with chronic lymphocytic leukemia increases the risk for other cancers by decreasing immune surveillance. This theory is consistent with the high incidence of aggressive B-cell lymphoma in other immune deficiencies such as AIDS. The transformation of chronic lymphocytic leukemia has some unique distinctions, however. Although other immunodeficiency states may progress to B-cell lymphoma, they do not develop acute lymphoblastic leukemia or multiple myeloma. Also, the B-cell lymphomas associated with immunodeficiency states are often initially oligoclonal and polyclonal and may be associated with Epstein-Barr virus infection [95-97]. No such evidence exists in chronic lymphocytic leukemia.

                The third possibility is that the initial abnormality that leads to the development of chronic lymphocytic leukemia also underlies development of these more aggressive B-cell cancers. For example, a variety of T-helper, T-suppressor, and natural killer cell abnormalities accompany and may antedate development of chronic lymphocytic leukemia [1]. Perhaps these cellular abnormalities also predispose to clonal expansion of other B-cell subsets, culminating in these more aggressive B-cell cancers.

                The B-cell cancers genetically related to chronic lymphocytic leukemia are also of interest. Elsewhere, we reviewed data suggesting that transformation in chronic lymphocytic leukemia may occur in a B stem cell. We also reviewed data suggesting that small numbers of mature B cells, including plasma cells, are produced by the leukemia clone, even in typical cases of chronic lymphocytic leukemia [74]. These data may explain the plasticity of morphologic expression of the B-cell cancers that develop in persons with chronic lymphocytic leukemia.

                In summary, both clonal evolution and independent transforming events account for the high incidence of more aggressive B-cell cancers in persons with chronic lymphocytic leukemia. More detailed analyses of these cases of transformation may provide insights into what causes chronic lymphocytic leukemia and how it and other cancers progress. The B-cell cancers have the unique feature of immunoglobulin gene rearrangement and expression, which can be used to study genetic relatedness between B-cell cancers. Because of this property, persons with chronic lymphocytic leukemia provide an important and unique opportunity to study cancer development and evolution in humans.

                Finally, the potential uses of these new technologies to treat B-cell cancers remains to be fully explored. For example, anti-idiotypic antibodies can be regarded as tumor-specific and therefore offer a potential novel therapeutic approach to the treatment of B-cell cancers. Infusing unlabeled antibody might destroy tumor cells by activation of complement and antibody-dependent cellular cytotoxicity. Alternatively, these antibodies could be labeled with radioisotopes delivering radiation directly to the tumor cells. Interestingly, some anti-idiotype antibodies generated for a specific patient's tumors crossreact with tumor cells from other persons with B-cell tumors [98, 99]. These are called shared idiotypes and may obviate the need to develop specific anti-idiotype antibodies for each person. Another approach is to recover immunoglobulin from a person's tumor and to inject it, mixed with an immune adjuvant, into the same person. This treatment could result in the development of an anti-idiotype immune response to the patient's tumor. All of these approaches are being studied [100-102].

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                Appendix: Glossary of Terms

                Anti-idiotype antibody: An antibody that binds specifically to the idiotype (see idiotype).

                Clone: A tumor grown from a single somatic cell of its parent and genetically identical to it.

                Complementarity: Correspondence in reverse of part of one molecule to part of another, as in the arrangement of chemical groups and electric charges that enable a combining group of an antibody to combine with a specific determinant group of an antigen or hapten.

                Idiotype: The molecular structure and confirmation in the variable region of an antibody that has had its antigenic specificity confirmed.

                Isotype: Any of the categories of immunoglobulins determined by their physiochemical properties and antigenic characteristics that occur in all individuals of a species (for example, IgG ).

                Karyotype: The chromosome characteristics of a cell.

                Transformation: An act, process, or instance of transforming or being transformed. For instance, a normal cell into a malignant cell or one malignant cell type transforming into another malignant cell type.

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                Abbreviation

                CDR: complementarity-determining regions

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