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The study of different clones of myeloid leukemic cells has shown that in addition to DI clones there are differentiation defective clones called D- clones (15, 56, 66-71). Some Dclones are induced by a normal myeloid differentiationinducing cytokine to an intermediate stage of differentiation that then slows down the growth of the cells, and others could
not be induced to differentiate even to this intermediate stage. It was suggested that DI clones are the early stages of leukemia and that the emergence of D- clones may be later stages in the progression of malignancy (53). Even these' D- cells can be induced to differentiate by other compounds, either singly or in combination, that can induce the differentiation program by alternative pathways. The stopping of cell multiplication by
inducing differentiation by these alternative pathways bypasses the genetic changes that inhibit response to the normal differentiation-inducing cytokine (reviewed in refs. 25-27 and
58). Studies on the genetic changes in D- clones of myeloid leukemias have shown that differentiation defectiveness may be due to changes in homeobox genes. These include rearrangement of the Hox-2.4 homeobox gene which results in abnormal expression of this gene in the leukemic cells (72). This abnormal expression of Hox-2.4 inhibits specific pathways of myeloid cell differentiation (73). In other leukemias with a deletion in one chromosome 2 (57) there is a deletion of one copy of Hox-4.1 (74).