Activating transcription factor 4 (ATF4) is a stress-induced transcription factor that is frequently upregulated in cancer cells. ATF4 controls the expression of a wide range of adaptive genes that allow cells to endure periods of stress, such as hypoxia or amino acid limitation. However, under persistent stress conditions, ATF4 promotes the induction of apoptosis. Recent advances point to a role for post-translational modifications (PTMs) and epigenetic mechanisms in balancing these pro- and anti-survival effects of ATF4. We review here how PTMs and epigenetic modifiers associated with ATF4 may be exploited by cancer cells to cope with cellular stress conditions that are intrinsically associated with tumor growth. Identification of mechanisms that modulate ATF4-mediated transcription and its effects on cellular metabolism may uncover new targets for cancer treatment.

Transcription factor Growth factor independence 1 (Gfi1) is required for multilineage blood cell development, from stem and progenitor cells to differentiated lymphoid and myeloid cells. Gfi1 expression is rapidly induced by cytokines that control both the adaptive and innate immune systems. Gfi1 itself represses the expression of genes implicated in cell survival, proliferation and differentiation. Changes in Gfi1 expression and function have not only been implicated in neutropenia, allergy, autoimmunity and hyperinflammatory responses, but also in lymphoma and more recently in the development of leukemia. In this study, we review how Gfi1 and its paralogue Gfi1b control the development of blood cells, discuss how changes in Gfi1 and Gfi1b function contribute to hematological disease and report on the molecular function of these proteins.

Since the identification of B‐cell translocation gene 1 (BTG1) and BTG2 as antiproliferation genes more than two decades ago, their protein products have been implicated in a variety of cellular processes including cell division, DNA repair, transcriptional regulation and messenger RNA stability. In addition to affecting differentiation during development and in the adult, BTG proteins play an important role in maintaining homeostasis under conditions of cellular stress. Genomic profiling of B‐cell leukemia and lymphoma has put BTG1 and BTG2 in the spotlight, since both genes are frequently deleted or mutated in these malignancies, pointing towards a role as tumor suppressors. Moreover, in solid tumors, reduced expression of BTG1 or BTG2 is often correlated with malignant cell behavior and poor treatment outcome. Recent studies have uncovered novel roles for BTG1 and BTG2 in genotoxic and integrated stress responses, as well as during hematopoiesis. This review summarizes what is currently known about the roles of BTG1 and BTG2 in these and other cellular processes. In addition, we will highlight the molecular mechanisms and biological consequences of BTG1 and BTG2 deregulation during cancer progression and elaborate on the potential clinical implications of these findings.

Targeting tumor cell metabolism is an attractive form of therapy, as it may enhance treatment response in therapy resistant cancers as well as mitigate treatment-related toxicities by reducing the need for genotoxic agents. To meet their increased demand for biomass accumulation and energy production and to maintain redox homeostasis, tumor cells undergo profound changes in their metabolism. In addition to the diversion of glucose metabolism, this is achieved by upregulation of amino acid metabolism. Interfering with amino acid availability can be selectively lethal to tumor cells and has proven to be a cancer specific Achilles' heel. Here we review the biology behind such cancer specific amino acid dependencies and discuss how these vulnerabilities can be exploited to improve cancer therapies.

Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL.