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Cell Surface Markers in Acute Lymphoblastic Leukemia* F ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 10, No. 3 Copyright © 1980, Institute for Clinical Science, Inc. Cell Surface Markers in Acute Lymphoblastic Leukemia* f G. BENNETT HUMPHREY, M.D., REBECCA BLACKSTOCK, Ph .D., AND JANICE FILLER, M.S. University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73126 ABSTRACT During the last nine years, two important methodologies have been used to characterize the cell surfaces of normal lymphocytes and malignant lym­ phoblasts. Normal mature T-cells have a receptor for sheep erythrocytes (E+) while mature B-cells bear membrane-bound immunoglobulin molecules (slg+). These two findings can be used to divide acute lymphoblastic leukemia of childhood into three major groups; B-cell leukemia (slg+ E -), which is rare (approximately 2 percent) and has the poorest prognosis, T-cell leukemia (slg~, E +) which is more common (10 percent) but also has a poor prognosis and null cell leukemia (slg~, E~) which is the most common (85 percent) and has the best prognosis. By the use of additional immunological methods, subgroups within T-cell leukemia and null cell leukemia have also been proposed. One of the most valuable of these additional methods is the detection of surface antigens. Three of the more commonly detected antigens currently being evaluated are (1) common leukemia antigen (cALL), (2) a normal B Lymphocyte antigen the la antigen (la) which is not generally expressed on most T lympho­ cytes and (3) a normal T lymphocyte antigen (T) not expressed on B lympho­ cytes. Within null cell leukemia, the most commonly identified and proba­ bly the largest subgroup is Ia+, cALL+, T”, E _, slg-. In another but smaller subgroup within null cell leukemia, the lymphoblasts contain cytoplasmic immunoglobulin but do not express surface immunoglobulins or E recep­ tors. This subgroup is designated pre B-cell leukemia. Subgroups with T-cell leukemia have also been suggested. These include T+ E~, T+ E+, in which the rosettes are thermolabile and T+ E+, in which the rosettes are thermostable. Whether qr not there are any prognostic differences in these three subgroups remains to be determined. Introduction homogeneous entity. However, a wide range of clinical responses to therapy ob­ Acute lymphoblastic leukemia (ALL) in served over the past two decades has children is morphologically a relatively suggested that ALL is a heterogeneous * This investigation was supported by Grant disease. Early extensive evaluation of Number CA11233, awarded by The National Cancer clinical and laboratory data identified a Institute, DHEW. number of prognostic factors such as age, f Address reprint requests To: Southwest Oncol­ ogy Group, Operations Office, Suite 100, 3500 Rain­ initial white count, presence or absence of bow Blvd., Kansas City, KS 66103. a mediastinal mass.23 While these prog- 169 0091-7370/80/0500-0169 $01.80 © Institute for Clinical Science, Inc. 1 7 0 HUMPHREY, BLACKSTOCK AND FILLER nostic factors have been of value, the immunoglobulin. A precursor cell of the search for surface markers as correlates of mature B-cell has been demonstrated to major groups within ALL has dominated have cytoplasmic immunoglobulin (clg) leukemia research for the past nine years but not surface immunoglobulins (slg) and is the principle topic of this review. and is designated a pre-B-cell. A mature In the early 1970’s, several laboratories lymphocyte has receptors for sheep eryth­ reported that normal human peripheral rocytes (E). For human cells, receptor for blood T-lymphocytes spontaneously complement and the Fc portion of IgG formed rosettes with sheep erythrocytes. were initially thought to be limited to During the same period of time, the dem­ B-lymphocytes. Subsequent research has onstration of surface immunoglobulin on shown that these two receptors can also peripheral B-cells became a common lab­ reside on subpopulations of some T-cells oratory procedure. These two discoveries and are therefore not used independently were applied to bone marrow lympho­ to identify either T or B-cells. blasts obtained from children with leukemia and have resulted in the iden­ The Major Groups Within ALL tification of three major groups within this disease: T-cell leukemia, B-cell leukemia For the purpose of discussion, ALL will and null cell leukemia. be divided into three major groups. T-cell, Other methodologies have also been null cell and B-cell leukemia. T-cell applied to ALL cells to identify further leukemia will be limited to those cases subgroups based on cytogenetics, cell cul­ that are E-receptor positive. No distinc­ ture growth characteristics, etc. Subtle tion will be made in this section as to morphological differences based on light thermolabile and thermostable subgroups microscopy have been used to charac­ of E-receptor positive cases. B cell disease terize blast cells. An international will be limited to those cases that are sur­ cooperative committee proposed the face immunoglobulin positive. In some of French-American-British (FAB) classifi­ the early literature, the presence of a Fc cation of ALL which subdivides ALL into receptor or complement receptor was three morphological types: Lj, L2 and L3. used to identify cases designated B-cell These morphological groups have been disease or B-cell leukemia. As both of related to surface marker studies and have these receptors can be found on both been shown recently to be of prognostic T-cells as well as B-cells, these markers significance.38 will not be accepted as characterizing The application of human lymphocyte B-cell disease for this discussion. differentiation and subpopulations to the Null cell disease will include those immunological diagnosis of other disor­ cases that do not express either the ders has been the subject of recent re­ E-receptor or have detectable surface views which are recommended for a more immunoglobulin (slg). In many articles, detailed background study of this impor­ null cell disease is diagnosed by exclusion tant and rapidly developing area of clini­ and is referred to as non-T non-B cell cal and laboratory research.20,46’50 disease. Surface Markers B-C e l l L e u k e m i a Cell surface markers have been used to B-cell leukem ia is the rarest o f the major identify functional subdivisions of lym­ or well established groups. This group has phocytes. For example, B-lymphocytes a very poor prognosis, as response to are identified by the presence of surface chemotherapy results in short remis­ CELL SURFACE MARKERS IN ACUTE LYMPHOBLASTIC LEUKEMIA 171 sions.4,10,30,15 T he patients tend to be older a high white cell count, mediastinal mass and a male predominance has been and older patient population, were known suggested.30 Although leukemic presenta­ to be of poor prognostic significance prior tion of Burkitt’s lymphoma is unusual, to the application of markers to ALL. there are a number of characteristics The remission induction rate of T-cell which suggest that B-cell leukemia and leukemia is similar to that of null cell dis­ Burkitt’s lymphoma are closely related or ease with both groups responding well to are even the same disease. For example, a vincristine/prednisone therapy. On 14q+ chromosome has been reported in standard ALL therapies, such as both B-cell leukemia and Burkitt’s lym­ 6-mercaptopurine and methotrexate, a phom a.30,51 The morphology of both is of short median duration of remission has the L3 type and malignant B-cells have been reported by a number of investiga­ been described as “Burkitt cells.” tors. When alkylating agents such as cyc­ lophosphamide or an anthracycline such N u l l C e l l L e u k e m i a as adriamycin is added to the maintenance regimen, longer median durations of re­ Approximately 85 percent of childhood mission are being reported .17,58 ALL is classified as null cell leukemia. Null cell leukemia has the best prognosis C ytochemical M e t h o d s a s of the major groups. The clinical charac­ R e l a t e d T o M a j o r G r o u p s teristics of this group include those gener­ ally associated with good prognosis such Cytochemical methods have been used as younger age, lack of tumor mass at pres­ for a number of years to classify the entation, and a lower initial white cell leukemias. This has been especially true co u n t.4,10,30,24 T he bone m arrow is thought for the differential diagnosis of acute to be the origin of null cell leukemia. myeloblastic leukemia from acute lym­ These patients respond well to both in­ phoblastic leukemia. Recently, there has duction and remission therapy. This is been a number of papers published that true for both median duration of remission have attempted to correlate surface mar­ and survival.4,10 kers with some enzyme systems in leukemic cells. In table I are summarized some of the T-C e l l L e u k e m i a recent studies in w hich both im m unologi­ T-cell leukemia accounts for approxi­ cal and enzyme markers in leukemia have m ately 10 percent of childhood cases of been studied. Leukemia cells with T-cell ALL.22,30 T-cell leukemia has a poorer surface markers have a markedly reduced prognosis than null cell leukemia, but a 5-nucleotidase activity, while null lym­ better one than B-cell leukemia. T-cell phoblasts have normal levels of this en­ leukemia occurs more frequently in males zym e.44 One of the most widely studied than females and in older children, the enzymes is TdT .13 Elevated levels of TdT median age being 10 to 12 years in studies have been found in children with both limited to children.
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