The transcription factor NK2-related homeobox 1 (NKX2-1) is essential for normal lung development, and previous work has indicated that the amplification of NKX2-1 in a small subset of lung cancers is oncogenic. Two recent reports describe divergent roles for NKX2-1 in cancer: in one context this transcription factor is oncogenic and in another it functions as a suppressor of tumour progression.

Paediatric T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy that is characterized by the presence of specific genetic abnormalities; however, for 40% of cases the driving mutations remain undiscovered. Writing in Cancer Cell, Jules Meijerink and colleagues have uncovered a new genomic profile that is associated with the expression of NKX2-1.Expression profiling and cytogenetic analysis of 117 samples from paediatric patients with T-ALL identified two mutually exclusive T-ALL subtypes, neither of which possessed known oncogenic alterations. One of these subtypes exhibited maturation arrest at the CD1-positive cortical thymic stage and had high expression levels of NKX2-1. Correspondingly, molecular cytogenetic techniques, includingchromatin conformation capture on chip (4C) — a method that robustly detects reciprocal chromosomal rearrangements — in this subgroup identified five NKX2-1 (or homologous NKX2-2) rearrangements in seven of 12 cases. Support for an oncogenic role for NKX2-1 in this study was provided by its ability to transform fibroblast cells together with MYC or RAS.

However, the function of NKX2-1 seems to be more complex than that of a simple oncogene, as a recent Nature paper has indicated that Nkx2-1 can hinder lung cancer progression in mice. Tyler Jacks and colleagues induced lung cancer using lentiviral vectors expressing Cre to activate the expression of one copy of an oncogenic Kras transgene and to delete Trp53 in LSL-KrasG12D/+; Trp53flox/flox mice. Tracking genomic lentiviral integration sites enabled a comparison of expression profiles between metastatic and non-metastatic cells and revealed that Nkx2-1 is downregulated in advanced lung adenocarcinomas. Reduced Nkx2-1 expression correlated with high-grade, poorly differentiated adenocarcinoma, whereas Nkx2-1-expressing tumours were well-differentiated. Moreover, overexpression of Nkx2-1 was found to greatly limit the number of high-grade adenocarcinomas, and silencing of Nkx2-1 expression in lung cancer cells either intravenously injected or intrasplenically transplanted increasedlung and metastatic liver nodules, respectively. Furthermore, knockdown of Hmga2 — which is repressed by NKX2-1 — in Nkx2-1-negative cells significantly decreased metastatic seeding.

Thus, the dual role of NKX2-1 proposed by these studies emphasizes the importance of molecular profiling and characterization across not only malignancies, but also their stages.