Mechanism and therapeutic implication of RNA-modification-mediated codon-biased translation in acute myeloid leukemia

Among the 20 standard amino acids encoded by 61 codons, 18 are encoded by multiple synonymous codons. However, the synonymous codon usage is not random, as different organisms or different genes in an organism prefer using different synonymous codons; such a phenomenon is called codon bias. A mechanism, termed codon-biased translation, which involves adapting tRNA pools to meet the demands of translating stress- response mRNAs that utilize biased codons, is hijacked by cancer cells to support their survival/proliferation and therapeutic resistance, via facilitating the synthesis of essential oncogenic proteins with biased codons. However, the detailed mechanisms remain poorly understood. Acute myeloid leukemia (AML) is a type of common and fatal hematopoietic malignancies and over 70% of AML patients cannot survive over 5 years. Thus, there is a critical unmet clinical need to elucidate the molecular mechanisms driving leukemogenesis, particularly those governing leukemia stem/initiating cell (LSC/LIC) self-renewal and drug resistance, to develop more effective therapeutic strategies to treat unfavorable-risk AMLs. Our preliminary data suggests that ALKBH1, a Fe(II)/α-ketoglutarate (α-KG)-dependent dioxygenase, likely plays an essential tumor-promoting role in AML. Alkbh1 deletion significantly inhibited AML development and LSC/LIC self-renewal in the MLL-AF9-induced AML model. Notably, we revealed that ALKBH1 is totally dispensable for normal hematopoiesis, highlighting a unique therapeutic opportunity to target ALKBH1 in AML. Interestingly, our preliminary data suggests that ALKBH1 is likely a key regulator of codon-biased translation in AML through promoting RNA 5-formylcytosine (f5C) modification and thus facilitating codon-biased translation of oncogenic targets such as WDR43, which in turn likely promotes AML development/progression, LSC/LIC self-renewal and resistance to venetoclax (a potent BCL2 inhibitor). Based on our preliminary results, we hypothesize in codon-biased especially Aims that ALKBH 1 orchestrates C modifications tRNA and mRNA, facilitating LSC/LIC self-renewal and driving AML initiation and progression via f 5 C-mediated translation, and that targeting ALKBH1 represents a promising therapeutic strategy , alone and in combination with venetoclax, in treating AML by eradicating LSCs/LICs . We propose three Specific to test our central hypothesis: (1) f5 Determine the role of ALKBH1 in AML pathogenesis and drug response; (2) Decipher the RNA-modification-related mechanism by which ALKBH1 facilitates codon-biased translation in AML; and (3) Evaluate the therapeutic potential and underlying mechanism(s) of pharmacologically targeting ALKBH1 in AML. Overall, our proposed studies will substantially advance our understanding of the fundamental biology and underlying molecular mechanism(s) of ALKBH1-mediated epitranscriptomic (RNA modification) changes in tRNA and mRNA and their crosstalk in facilitating codon-biased translation, leukemogenesis and drug resistance. This project will also lead to the development of effective novel strategies to treat unfavorable- risk AMLs by targeting ALKBH1 signaling. Thus, our project is of high novelty and translational significance. Project Number: 1U01CA305196-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jianjun Chen (+1 co-PI) | Institution: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE, DUARTE, CA | Award Amount: $941,798 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZCA1 SRB-P (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11225452