Editorial: Feel the burn: blocking galectin-12 helps leukemic cells differentiate while staying lean.

Neoplastic disease continues to represent one of the most formidable challenges in modern medicine. Many neoplastic lesions stem from the cumulative outcome of a variety of genetic mutations, allowing cells to rely on multiple and often redundant pathways to sustain undesirable growth [1]. In contrast, several forms of leukemia appear to result from unique translocation events that lead to the formation of a distinct gene product capable of driving neoplastic transformation. APL, a classic example of this phenomenon, results from a translocation event between chromosomes 15 and 17 that fuses the PML gene with RARa. The chimeric protein product of this translocation causes significant transcriptional repression, which reduces the expression of many genes needed for appropriate leukocyte differentiation [2]. These poorly differentiated cells accumulate, resulting in the increased number of immature promyelocytic blasts observed in patients with APL. Although APL can be life threatening, the gene product of the 15:17 translocation (PML-RARa) can be targeted by ATRA, resulting in a 72–90% response rate in patients with APL [2]. ATRA serves as a ligand for the RARa domain of the chimeric PML-RARa protein. Engagement by ATRA allows de-repression of PML-RARa-inhibited genes and facilitates the expression of key factors required for APL differentiation [2]. Once differentiated, APL cells become sensitive to the normal turnover programs responsible for leukocyte homeostasis. Thus, ATRA removes the developmental block experienced by APL and in so doing, directly facilitates the very leukocyte differentiation needed to successfully treat this neoplastic disease. Unfortunately, although ATRA represents one of the most successful examples of targeted chemotherapy, not all patients respond to ATRA. This heterogenous response, in part, reflects 15:17 translocation variants that may produce slightly different translocation products, in addition to other types of translocations that generate entirely distinct RARa chimeric proteins [2]. However, even patients who appear to have acquired the same 15:17 translocation can display varied responses to ATRA treatment. In the postgenomic era of modern medicine, understanding the molecular basis of resistance of APL to ATRA is necessary, not only to predict treatment outcome accurately but also, to tailor therapy to treat these patients most optimally. To address this challenge, Xue et al. examined the expression of galectin-12, a unique regulator of cellcycle progression, in different types of acute myeloid leukemia [3, 4]. They found that galectin-12 displays significantly increased expression, specifically within the APL subtype of acute myeloid leukemia, implying a unique role for galectin-12 in APL pathogenesis. To examine this possibility, Xue et al. [3] performed a classic knockdown of galectin-12 in the APL cell line, NB4, to determine the fate of APL in the absence of this protein. Knockdown of galectin-12 alone did not impact APL differentiation or survival at baseline, strongly suggesting that galectin-12 does not appear to play a critical role in the PML-RARa-mediated developmental arrest of APL. However, knockdown of galectin-12 did render NB4 cells more sensitive to ATRA-induced differentiation, as evidenced by the increased development of neutrophil-like morphology, CD11b expression, and the assembly of key factors, such as P47, required for production of reactive oxygen species (Fig. 1). As a result, this study suggests that galectin-12 may serve as a unique inhibitor of ATRA therapy in patients experiencing APL and therefore, may serve as a useful additional target in patients with APL refractory to ATRA treatment. In addition to providing important insight into the impact of galectin-12 on the sensitivity of APL to ATRA, these results lay an important framework for understanding fundamental biologic activities of galectin-12. Galectins originally received their name as a result of their unique ability to regulate biologic activity through recognition of distinct carbohydrate ligands [5]. Consequently, the vast majority of studies seeking to elucidate galectin function has focused on their