Paired-like homeobox 2b (PHOX2B)

Paired-like homeobox 2b (PHOX2B) is a master regulator transcription factor essential for the development of the autonomic nervous system, particularly noradrenergic neurons and circuits governing respiration [5, 6]. It is primarily expressed in the peripheral autonomic nervous system and specific brainstem nuclei [1, 5]. Mutations in PHOX2B, such as polyalanine expansions or frameshift mutations, are the primary cause of Congenital Central Hypoventilation Syndrome (CCHS) and are also linked to Hirschsprung disease and neuroblastoma [4, 9, 13]. In neuroblastoma, PHOX2B is often overexpressed and serves as a specific diagnostic and prognostic biomarker, as well as a marker for minimal residual disease [3, 7, 16]. While traditionally considered difficult to target directly, recent research has identified small molecules like chloroquine and mycophenolate mofetil that can down-regulate its expression, offering potential therapeutic avenues for neuroblastoma [3, 7]. However, because of its critical role in maintaining autonomic functions like breathing, therapeutic modulation of PHOX2B requires careful consideration of potential safety risks related to respiratory and autonomic control [4, 5]. Furthermore, its role as a metastasis suppressor in certain tumor contexts suggests that its inhibition might have complex effects on disease progression [16]. Overall, PHOX2B represents a critical molecular determinant of autonomic identity and a promising, albeit challenging, target for neuroblastoma therapy [3, 12].

Other names

Paired mesoderm homeobox protein 2BNBPhoxPMX2BNBLST2Paired mesoderm homeobox 2bPHOX2B homeodomain protein

Down-regulation of PHOX2B gene expression at the transcriptional and post-transcriptional levels [3, 7, 8]