The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastomas

Neuroblastoma is derived from the sympathetic nervous system and might aris e as a result of impaired differentiation, retaining the neuroblastic tumor cells in the cell cycle. Thus, to understand the genesis of neuroblastoma, the study of mechanisms and genes regulating normal sympathetic developmen t is of potential interest. The basic helix-loop-helix transcription factor s human achaete-scute homolog-l (HASH-1) and deciduum, heart, autonomic ner vous system, and neural crest derivatives (dHAND) are expressed in the symp athetic nervous system of embryonic mice and chicken, with undetectable pos tnatal expression. By in situ hybridization technique, we show that dHAND w as expressed by human sympathetic neuronal and extra-adrenal chromaffin cel ls throughout embryonic and fetal life, and was initially expressed in imma ture chromaffin cells of the adrenal gland. With overt chromaffin different iation, dHAND was down-regulated. HASH-I, in contrast, was expressed in hum an sympathetic cells only at the earliest embryonic ages examined (Week 6.5 to 7). All examined neuroblastoma specimens (25/25) and all cell lines (5/ 5) had detectable dHAND mRNA levels. HASH-I expression in tumor specimens w as more restricted, although all cell lines (5/5) were HASH-1-positive. The se results show that neuroblastoma tumors have retained embryonic features, suggesting that many neuroblastomas are blocked at an early stage of norma l development when HASH-1 and dHAND are expressed. dHAND also appears to be a reliable and potentially useful clinical diagnostic marker for neuroblas toma, because expression was not dependent on tumor or differentiation stag es and other pediatric tumors were dHAND-negative.