Four patients with acute nonlymphocytic leukemia who were heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase (G6PD) were studied to determine the numbers and types of progenitor cells in which the disease arose. Both forms of enzyme were found in normal tissues, but the malignant blast cells showed only one G6PD, indicating that the disease was clonal at the time of testing. The observations that normal erythroid cells were present in two young patients at diagnosis and relapse indicate that the clone suppressed expression of normal granulopoiesis but did not prevent normal erythroid differentiation. In contrast to this situation, in two elderly patients, the disease involved stem cells multipotent for granulocytes, red cells, and platelets. These results indicate that acute nonlymphocytic leukemia is heterogeneous. In some patients, the disease is expressed in cells with differentiation restricted to the granulocyte-monocyte pathway; in others, it involves stem cells capable of differentiating to granulocytes-monocytes, platelets, and erythrocytes. This heterogeneity may reflect differences in causation and could have prognostic and therapeutic importance.

Bone marrow lymphoblasts from 109 children admitted with untreated acute lymphoblastic leukemia (ALL) were tested for spontaneous rosette formation with sheep erythrocytes. Twenty-six children (24%) had lymphoblasts that formed rosettes (E+). Of 13 initial clinical characteristics, 8 were significantly associated with E+ lymphoblasts: mediastinal enlargement (86% of patients E+), leukocyte counts over 100 X 10(9)/liter (65% E+), nodes greater than 2 cm in any diameter (65% E+), age over 5 yr (46% E+), hemoglobin over 8 g/dl (44% E+), hepatomegaly greater than 5 cm (38% E+), boys (35% E+), and lymph node enlargement outside of the cervical area (28% E+). Spleen size, initial platelet counts, and periodic acid-Schiff scores did not distinguish E+ from E- patients. Since few patients were black and few presented with central nervous system leukemia, the association of these two characteristics with E+ blasts could not be determined. A hierarchical classification scheme and a linear logistic regression model were used to define the patterns of characteristics associated with E+ lymphoblasts. The initial clinical characteristics and the poorer course of E+ patients suggest that ALL comprises at least two biologically and clinically distinct types. The E+ ALL may result from a leukemic transformation of a non-Hodgkin lymphoma.

Adherent cells from long-term marrow cultures from 23 individuals were transformed with wild-type simian virus 40 (SV40). After transformation, cloned cell lines were developed that even after rigorous subcloning invariably produced both stromal cells and round cells. The stromal cells expressed cytoskeletal filaments similar to those of long-term marrow culture adherent cells and produced interstitial and basal lamina collagen types. The round cells had the electron microscopic appearance of primitive hematopoietic cells and when examined with cytochemical stains and monoclonal antibodies to hematopoietic differentiation antigens had reaction patterns suggestive of cells from several lineages. Most round cells expressed the pan- hematopoietic T-200 determinant, and lesser percentages expressed the early T cell antigens CD-1 and CD-3, HLA-DR determinants, the monocytic antigen recognized by Leu M3, and the myeloid antigens detected by monoclonal antibodies 1G10 and 12.8. In addition, when plated in semisolid medium in the presence of a source of colony-stimulating activity, up to 11% of the cells formed colonies consisting of blastlike cells that also expressed hematopoietic cell surface determinants. The data suggest that adherent cells in long-term marrow cultures contain a cell that after transformation by SV40 obligately produces cells with hematopoietic as well as stromalike features.

We have analyzed the pretreatment 3H-thymidine labeling indices in blood and marrow blast cells from 97 children with acute lymphoblastic leukemia (ALL) and circulating blasts. The median marrow labeling index (LI) was 6.2% (range 0.8%--32.7%) and the median blood LI, 3.2% (range 0.3%--20%). Blood LI was significantly correlated with leukocyte count and rosette-forming (E+) lymphoblasts but not with central nervous system leukemia or thymic mass at diagnosis. Marrow LI was related to E+ blasts only. In children with E+ leukemia, both blood and marrow LIs were significantly higher than values for other ALL subtypes (p less than 0.01) excluding undifferentiated ALL, which was characterized by an increased blood LI. Eighteen patients had a blood LI that either equaled or exceeded the marrow LI; apart from age, the clinical features, blast phenotypes, and treatment responses of this group were similar to those of patients with blood LI less than marrow LI. Among 51 patients assessed for treatment response, the estimated median length of remission was significantly shorter for those with a blood LI greater than 4% (p = 0.002) or a marrow LI greater than 6% (p = 0.011). By Cox-regression analysis, the pretreatment proliferative activity of blood and marrow blasts, unlike other initial features studied, added significant prognostic information to leukocyte count in these patients with circulating blasts. The findings provide a cogent explanation for the differential clinical responsiveness of commonly recognized ALL subclasses.

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