A HEMATOPOIETIC PROTEIN-TYROSINE-PHOSPHATASE (HEPTP) GENE THAT IS AMPLIFIED AND OVEREXPRESSED IN MYELOID MALIGNANCIES MAPS TO CHROMOSOME LQ32.1

Tyrosine phosphorylation is an important regulator of cell growth and differentation reflecting the interaction of protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP). Although excessive PTK activity can result in hematopoietic cell transformation, perturbation of either of these two modulators may result in uncontrolled cell gro wth. Myeloid cells are responsive to growth factors and cytokines that induce tyrosine phosphorylation and can become ligand independent whe n endogenous PTKs become dysregulated. Specific PTPs, through mutation or altered expression, may enhance PTK activities and also cause myel oid ligand independence, though this has not yet been demonstrated. We have previously reported the isolation of a hematopoietic specific cy toplasmic PTP (HePTP). We now report that this gene maps to chromosome 1q32.1 utilizing fluorescent in situ chromsomal hybridization (FISH). this site is frequently amplified in preleukemic myeloproliferative d iseases. FISH analysis of a patient with myelodysplastic syndrome char acterized by myeloid hypoplasia and monocytosis reveals triplication o f the HePTP gene on one allele with elevated protein expression in neo plastic myelomonocytic cells. Elevated expression is also identified i n blasts from some patients with acute leukemia. These observations pr ompted us to examine the experimental effects on cell growth of HePTP overexpression. Though normal myeloid cells show minimal HePTP express ion, air hematopoietic cell lines tested show high expression of HePTP . Gene transfer of HePTP into NIH 3T3 cells was therefore performed, w hich caused altered cell morphology, disorganized growth, anchorage in dependent colony formation and subtle differences in the pattern of ty rosine phosphoproteins compared to control cell lines. We conclude tha t amplification and overexpression of HePTP may be an important cofact or contributing to abnormal myeloid cell growth.