SELECTIVE EXPRESSION OF HEAT-SHOCK GENES DURING DIFFERENTIATION OF HUMAN MYELOID LEUKEMIC-CELLS

Several studies have indicated a role for heat shock proteins during development and differentiation. In these studies we have examined the patterns of activation of the HSP-70A, HSP-70B, HSP-70B' and HSP-28 mRNAs and proteins during the differentiation of immature human leukemic cells to more mature progenitors by several differentiation-inducing agents. K562 cells activate the mRNA for HSP-70A, HSP-70B' and HSP-28 genes in the presence of hemin or sodium butyrate as cells differentiate into late erythroblasts. K562 cells become progressively more resistant to killing by heat shock during their differentiation to late erythroblasts. Further, selective inhibition of HSP-70A by antisense oligonucleotides to reduce HSP-70 kDa accumulation results in consistent reduction of hemoglobin production by 25-30% in K562 cells exposed to hemin. HL-60 cells differentiate into mature macrophages within 3 days foliowing addition of PMA. HSP-70A m RNA levels increase with in the first 2 h of PMA treatment and remain elevated for up to 3 days during the cells' gradual differentiation into mature macrophages. PMA and sodium butyrate treatment also cause elevated levels of HSP-28 mRNA expression; this increase is barely detectable at 24 h but is considerable at 72 h when about 90% of HL-60 cells are differentiated into mature macrophages or monocytes. These studies show that HSP-70A, HSP-70B' and HSP-28 may have specific roles during the differentiation of blood cell progenitors into erythrocytes or macrophages. Further, differentiation alters the thermal sensitivity of leukemic cells.