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Expression of Neurogenic Basic Helix-Loop-Helix Genes in Primitive Neuroectodermal Tumors¹

Departments of Neurological Surgery [R. C. R., M. S. B.], Biological Structure [R. C. R., O. B-M., T. A. R.], and Neurology [S. J. T.], The University of Washington School of Medicine, Seattle, Washington 98195; Division of Molecular Medicine, The Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 [S. J. T., J. M. O.]; and Divisions of Neurological Surgery [R. C. R.] and Pediatric Hematology-Oncology [J. M. O.], The Children's Hospital and Medical Center, Seattle, Washington 98105

The basic helix-loop-helix (bHLH) class of transcription factors plays a pivotal role in tissue-specific determination and differentiation. Moreover, dysregulated expression or loss of function of these factors contributes to leukemogenesis and solid tumor development. Neurogenesis is regulated by genes of the NEUROD/atonal and ACHAETE SCUTE families. We analyzed expression of human NEUROD1, NEUROD2, NEUROD3, and ACHAETE SCUTE 1 (HASH1) in cerebellar and cerebral primitive neuroectodermal tumors (PNETs), gliomas, and cell lines derived from a variety of neuroectodermal tumors by Northern analysis and in situ hybridization. NEUROD1 was expressed in each of the 12 medulloblastoma specimens, whereas NEUROD2 and NEUROD3/neurogenin were expressed in partly overlapping subsets of medulloblastomas. All of the tumors that presented with distant metastases expressed NEUROD3. The only other NEUROD3-positive tumor progressed early in treatment. Human ACHAETE SCUTE homologue (HASH1) was not expressed in medulloblastomas (infratentorial PNETs) but was expressed in three of five supratentorial PNETs. Neuroectodermal tumor cell lines derived from other sites (e.g., neuroblastoma and retinoblastoma) expressed NeuroD and ACHAETE SCUTE family members. No NEUROD message was detected in glial tumors or cell lines. Neurogenic bHLH transcription factor expression patterns suggest that specific family members may contribute to or reflect biological differences that arise during malignant transformation.

¹ This work was supported by NINDS NS 09458 (to R. C. R), NIH Grants ROI NS 28308 and NS 30304 (to T. A. R.), and the Seattle Children's Hospital, "Jesse's Perfect Peach" Neurooncology Research Fund (to J. M. O). R. C. R. was supported by the Charles A. Elsberg Fellowship in Neurological Surgery of the New York Academy of Medicine and by Neurosurgery Training Program Grant NO7144. S. J. T. was supported by an American Cancer Society grant. J. M. O. was supported by the Emily Dorfman Foundation through the American Brain Tumor Association.

² Present address: 59th Medical Wing/MKFN, Department of Neurosurgery, Wilford Hall Medical Center, 2200 Bergquist Drive, STE1, Lackland AFB, San Antonio, TX 78246-5300.

³ To whom requests for reprints should be addressed, at the Fred Hutchinson Cancer Research Center, Mailstop C3-168, 1100 Fairview Avenue, Seattle, WA 98109.

Received 1/14/97. Accepted 6/10/97.

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