Int J Clin Lab Res 23:70-77. 1993 9 Springer-Verlag 1993 The biology of stem ceU factor, a new hematopoietic growth factor involved in stem cell regulation Maria Cristina Gaili 2, Patricia-Jane V. Giardina 2, Anna Rita Migliaccio 1,3, and Giovanni Migliaccio 2,3 Istituto Superiore di Sanit',i, Rome, Italy 2 Division of Pediatrics, The New York Hospital, New York, USA 3 Lindsley F. Kimball Research Institute, New York Blood Center, New York, USA Summary. Recently, a new hematopoietic growth factor, stem cell factor, the ligand for the c-kit-proto-oncogene, has been cloned. The gene for this factor or for its recep- tor are deleted in two well known series of mice mutants which display pleiotropic stem cell defects. Therefore, this factor supposedly plays an important role in stem cell biology. This paper reviews some of the elegant genetic work which led to the discovery of the factor and of its receptor, the biological effects that this factor exerts in the hematopoietic system in normal individuals and in patients with Diamond-Blackfan anemia and speculates on some of its potential clinical applications. Key words: Stem cell factor - C-kit - Stem cells - Hema- topoiesis - Diamond-Blackfan Anemia duced mainly by activated T cells in response to media- tors of inflammation. Therefore, the physiological coun- terpart of the multilineage growth factors in the stroma is not known. Recently, a multilineage growth factor produced in the stroma has been identified and cloned by several groups [2, 11, 14, 20, 22, 30, 40, 42, 43]. It has been termed "mast cell growth factor," "stem cell factor," "kit-ligand" or "Steel factor." For genetic reasons dis- cussed in more detail later, we will use the term "Steel factor." This factor is highly potent, plays a key role in the process of hematopoietic differentiation and, there- fore, has potentially numerous clinical applications. In this study, we will review what is currently known about Steel factor and we will discuss its potential clinical use. Introduction Hematopoiesis is a daily process involving the interaction between stern and progenitor cells and growth factors released by the stromal cells in the marrow microenviron- ment. Several growth factors, which have been recently identified and cloned, are able to induce hematopoietic differentiation in vivo and in vitro. Studies using purified cells and chemically defined culture conditions have shown that the early steps of the differentiation process are regulated by the interactions between two classes of growth factors: the multilineage growth factors, such as interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the lineage- specific ones, such as M-CSF, G-CSF and erythropoietin (Epo) [25]. While the lineage-specific growth factors are produced by cellular components of the marrow micro- environment, the multilineage growth factors are pro- Correspondence to: G. Migliaccio, Laboratory of Hematopoietic Growth Factors, The New York Blood Center, 310 East 67th Street, New York, NY 10021, USA Genetic background Phenotype of mutations at the murine Steel and W locus White (W) and Steel (SI) are two distinct genetic loci which were identified first in the murine species on the basis of complementary semi-dominant mutations [35]. The W and SI mutations map on the murine chromo- somes 5 and 10, respectively [10, 11]. The mutations in- duce similar pleiotropic effects and target tissues with a stem cell-based organization such as the melanocytes, hematopoietic and germ cells. Counterparts of the W mutations have also been identified in rats (Ws) [29] and humans (piebald trait) [18]. The symbols "W" and "SI" usually identify the complete deletion of the loci; suffixes to these symbols identify alterations resulting from frame shift, stop codon or point mutations. Numerous alleles have been identified for both loci (Table 1). Unlike the majority of homozygous mutants which die at the embry- onic stage, the double heterozygotes (such as W/W v or S1/S1 d) are born viable and reach maturity [17, 35]. W/W v and SI/SI J have therefore been used to characterize the biological role of these loci in stem cell development [16, 17, 35].