THE CONTROL OF HEMATOPOIESIS AND LEUKEMIA - FROM BASIC BIOLOGY TO THECLINIC

Hematopoiesis gives rise to blood cells of different lineages througho ut normal life. Abnormalities in this developmental program lead to bl ood cell diseases including leukemia. The establishment of a cell cult ure system for the clonal development of hematopoietic cells made it p ossible to discover proteins that regulate cell viability, multiplicat ion and differentiation of different hematopoietic cell lineages, and the molecular basis of normal and abnormal blood cell development. The se regulators include cytokines now called colony-stimulating factors (CSFs) and interleukins (ILs). There is a network of cytokine interact ions, which has positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor necrosis factor (TNF). This multigene cytokine network provides flexibility dep ending on which part of the network is activated and allows amplificat ion of response to a particular stimulus. Malignancy can be suppressed in certain types of leukemic cells by inducing differentiation with c ytokines that regulate normal hematopoiesis or with other compounds th at use alternative differentiation pathways. This created the basis fo r the clinical use of differentiation therapy. The suppression of mali gnancy by inducing differentiation can bypass genetic abnormalities th at give rise to malignancy. Different CSFs and ILs suppress programmed cell death (apoptosis) and induce cell multiplication and differentia tion, and these processes of development are separately regulated. The same cytokines suppress apoptosis in normal and leukemic cells, inclu ding apoptosis induced by irradiation and cytotoxic cancer chemotherap eutic compounds. An excess of cytokines can increase leukemic cell res istance to cytotoxic therapy. The tumor suppressor gene wild-type p53 induces apoptosis that can also be suppressed by cytokines. The oncoge ne mutant p53 suppresses apoptosis. Hematopoietic cytokines such as gr anulocyte CSF are now used clinically to correct defects in hematopoie sis, including repair of chemotherapy-associated suppression of normal hematopoiesis in cancer patients, stimulation of normal granulocyte d evelopment in patients with infantile congenital agranulocytosis, and increase of hematopoietic precursors for blood cell transplantation. T reatments that decrease the level of apoptosis-suppressing cytokines a nd downregulate expression of mutant p53 and other apoptosis suppressi ng genes in cancer cells could improve cytotoxic cancer therapy. The b asic studies on hematopoiesis and leukemia have thus provided new appr oaches to therapy.