Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B-mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.

Cancer cells utilize codon-biased translation to fuel tumorigenesis and drug resistance; however, underlying mechanisms remain poorly understood. In this study, we show that ALKBH1 is overexpressed in acute myeloid leukemia (AML) and essential for leukemia stem cell/leukemia-initiating cell self-renewal and AML development/maintenance but dispensable for normal hematopoiesis. ALKBH1 enhances mitochondrial assembly/function and oxidative phosphorylation, crucial for AML survival/proliferation and resistance to venetoclax, a potent BCL2 inhibitor and widely used first-line targeted therapy for AML in the clinic. Mechanistically, ALKBH1 catalyzes 5-formylcytosine at tRNA wobble positions, reprograming decoding and facilitating codon-biased translation, a mechanism we term “epitranslatomic Midas touch,” which in turn drives leukemogenesis and drug resistance by promoting the synthesis of key oncogenic proteins like WDR43. Targeting ALKBH1, particularly together with venetoclax, exhibited potent antileukemia efficacy in preclinical models with favorable safety profiles. Collectively, our findings elucidate ALKBH1’s pivotal role in codon-biased translation and tumorigenesis and propose a novel therapeutic strategy for cancer treatment. Significance: This study uncovers that ALKBH1-driven tRNA-decoding reprogramming and codon-biased translation, termed “epitranslatomic Midas touch,” is crucial for leukemogenesis, leukemia stem cell/leukemia-initiating cell self-renewal, mitochondria structure/function, and resistance to venetoclax. Targeting ALKBH1, especially in combination with venetoclax, offers a promising therapeutic strategy to combat drug resistance in AML and potentially other ALKBH1-overexpressing cancers.