Improved treatment outcome has been achieved for acute nonlymphocytic leukemia (ANLL) using aggressive combination chemotherapy alone or followed by allogeneic bone marrow transplantation. Still, the biology of the disease is not well characterized and prognostic indicators have been of limited value. In a recent chemotherapy protocol for children with ANLL at this institution, we have found a significant relationship (p less than 0.001) between megakaryocyte size at diagnosis and treatment outcome. Patients with a predominance of small megakaryocytes had an extremely poor prognosis while those with a predominance of large megakaryocytes had a good prognosis and most have remained disease-free for more than three years. To explain this relationship between megakaryocyte size and treatment outcome, we hypothesize that the difference in the two groups relates to the level of differentiation of the hematopoietic progenitor cell in which the leukemic transformation occurred. To examine this hypothesis and understand the biology of this relationship, we propose to characterize abnormalities of size, concentration and DNA content of megakaryocytes and in vitro colony formation of their progenitors in childhood ANLL at diagnosis and determine how these characteristics relate to each other and to treatment outcome with the current treatment. Megakaryocyte size and concentration will be determined from marrow biopsy sections. DNA content of megakaryocytes will be determined by two-color flow cytometry after staining marrow cell suspension with platelet antiserum (specific label for megakaryocytes) and propidium iodide (DNA stain). Megakaryocyte colony formation will be assayed and characterized in vitro in semisolid media. To determine if megakaryocyte size in ANLL is related to whether the megakaryocytes arise from leukemic or normal progenitors, we will examine these cells at diagnosis for cytogenetic abnormalities present in the leukemic blasts. These studies should further evaluate the reliability of megakaryocyte size for predicting which patients will have long-term disease-free survival with combination chemotherapy alone. A reliable prognostic indicator for combination chemotherapy alone would be of benefit in choosing between ths treatment and bone marrow transplantation. In addition, this project will characterize the abnormalities of megakaryocytes in ANLL and determine whether megakaryocyte size in this disease is a reflection of the differentiation potential of the leukemic progenitors.
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