Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the arrest of myeloid differentiation and the clonal accumulation of immature myeloblasts. The balanced chromosomal translocation t(8;21)(q22;q22) defines a distinct clinical subtype of core-binding factor (CBF) AML and generates the RUNX1::RUNX1T1 (commonly termed RUNX1::ETO or AML1::ETO) fusion oncogene, which impairs erythropoiesis and blocks myeloid maturation1. However, murine models have demonstrated that expression of RUNX1::ETO alone is insufficient to induce overt leukemogenesis2. Instead, secondary genetic alterations are required to cooperate with RUNX1::ETO to drive full-blown t(8;21) AML2,3.

Leukemic cells extensively reprogram their metabolome to sustain rapid proliferation, survive within the hypoxic bone marrow niche, and mediate disease relapse4. This metabolic rewiring correlates strongly with clinical prognosis in AML, as specific metabolites and enzymatic regulators govern multiple pro-survival pathways5. In particular, metabolic adaptation is a principal mechanism through which dormant leukemic stem and progenitor cells evade chemotherapy and drive relapse following remission6. This phenomenon is especially prominent in t(8;21) AML, which exhibits a pronounced reliance on glucose metabolism mediated by key glycolytic regulators such as solute carrier family 2 member 3 (SLC2A3, encoding GLUT3) and platelet-type phosphofructokinase (PFKP)7,8,9. Notably, multiple rate-limiting glycolytic enzymes and glucose transporters are transcriptionally repressed by zinc finger and BTB domain-containing protein 7A (ZBTB7A).

ZBTB7A belongs to the ZBTB7 transcription factor subfamily, which also includes ZBTB7B and ZBTB7C, and plays an essential role in regulating gene transcription across hematopoiesis, oncogenesis, and cellular metabolism10. In normal hematopoiesis, loss of ZBTB7A reduces myeloid progenitor populations and impairs the repression of premature lymphoid differentiation11,12. Clinically, elevated ZBTB7A expression has been associated with favorable prognosis, even among patients with cytogenetically normal AML (CN-AML)13. In this review, we synthesize current evidence on how somatic ZBTB7A mutations cooperate with the RUNX1::ETO fusion oncoprotein to drive metabolic reprogramming and leukemogenesis in t(8;21) AML.

This article is a narrative review based on a comprehensive literature search conducted in PubMed and Google Scholar up to December 2025. Search terms included combinations and synonyms of "ZBTB7A" (including ZBTB7, POKEMON, LRF, and FBI-1), "metabolism", and "t(8;21) AML" (including RUNX1::RUNX1T1, RUNX1::ETO, RUNX1/RUNX1T1, RUNX1/ETO, AML1/ETO, AML1/MTG8, AML1::ETO, and AML1::MTG8). Peer-reviewed original research articles and published conference abstracts fulfilling all three search domains were selected for primary analysis. For studies matching two or fewer search domains, flexible inclusion criteria were applied to capture mechanistic findings in solid tumor or hematopoietic models with direct translational relevance to t(8;21) AML. The experimental models, specific ZBTB7A genetic alterations, metabolomic assays, and functional outcomes identified across the selected studies are summarized in Table 1 and illustrated schematically in Figure 1.

ZBTB7A—also referred to as POKEMON, FBI-1, LRF, and OCZF—is a transcriptional repressor encoded by the ZBTB7A gene located on human chromosome 19p13.314. The gene produces two transcript variants that encode an identical 584-amino-acid protein with an approximate molecular weight of 86 kDa15. ZBTB7A is a member of the BTB/POZ and Krüppel-type (POK) family of transcription factors, which are structurally defined by two conserved functional regions: an N-terminal broad-complex, tramtrack, and bric-à-brac/poxvirus and zinc finger (BTB/POZ) domain (residues 34–101) and a C-terminal array of four Krüppel-like C2H2 zinc finger (ZF) domains (ZF1–ZF4; residues 382–490). The BTB/POZ domain mediates homodimerization, heterodimerization, and the recruitment of transcriptional co-repressor complexes, whereas the C-terminal ZF domains recognize and bind specific promoter DNA sequences to repress target gene transcription16.

Proper nuclear import of ZBTB7A is governed by a nuclear localization signal (NLS), which is indispensable for its transcriptional regulatory activity10. Ren et al. (2023) mapped this NLS to an arginine- and lysine-rich motif located immediately downstream of the fourth ZF domain at residues 497–50410. Like other POK family members such as BCL6 and PLZF, ZBTB7A orchestrates diverse biological processes, most notably lineage commitment in hematopoiesis, tumorigenesis, and cellular energy metabolism17.

Somatic mutations in ZBTB7A can disrupt its subcellular localization and DNA-binding capacity, thereby abrogating its transcriptional repressor function13. Because the C-terminal region harbors both the ZF array and the NLS, truncating mutations upstream of residue 497 eliminate both DNA binding and nuclear targeting. Specifically, the frameshift variant ZBTB7A A175fs and the nonsense variant ZBTB7A R377X, both of which terminate the polypeptide prior to ZF1, exhibit pronounced cytoplasmic mislocalization in U2OS osteosarcoma cells compared with wild-type (WT) ZBTB7A13,18.

Conversely, missense mutations within the ZF domains preserve the downstream NLS and largely retain normal nuclear localization. In fluorescence localization assays, R402 missense variants (ZBTB7A R402C and ZBTB7A R402H) localized predominantly to the nucleus, with only a minor fraction detected in the cytoplasm compared with truncating mutants13. Consistently, the ZF1 missense variants R399L, R402H, and H404R localized to the nucleus in HEK293 cells19. Despite intact nuclear import, these ZF1 variants failed to bind the promoter regions of GLUT3 (SLC2A3) and PFKP, whereas the N-terminal non-ZF variant P14S retained promoter-binding activity, demonstrating that ZF missense mutations cause loss of function by abolishing DNA recognition rather than altering nuclear localization19. An earlier study similarly established that ZBTB7A R399L is defective in binding the GLUT3, PFKP, and PKM promoters20. This mechanistic distinction is corroborated by quantitative biophysical DNA-binding analyses reported by Ren et al. (2023), in which DNA-binding affinity was reduced by more than 50-fold for R402C and more than 12-fold for G395C (both within ZF1), by approximately 5- to 6-fold for R402H (ZF1) and K424T (ZF2), and by approximately 4-fold for the frameshift variant R458fs (within ZF3)10. Notably, R458fs exhibited the mildest intrinsic DNA-binding defect among the tested mutants but lacked the downstream NLS, underscoring that cytoplasmic mislocalization is a specific consequence of NLS loss rather than a general feature of ZF domain mutations.

Somatic ZBTB7A mutations show a striking specificity for t(8;21) AML. Hartmann et al. (2016) identified ZBTB7A mutations in 23.2% (13/56) of patients with t(8;21) AML13. In that cohort, a numerically higher proportion of patients with mutated ZBTB7A experienced disease relapse (4/13; 30.8%) compared with patients harboring WT ZBTB7A (5/43; 11.6%); however, this difference did not reach statistical significance (Fisher's exact test, p = 0.189; odds ratio 3.38, 95% confidence interval 0.75–15.17) and warrants validation in larger prospective cohorts. By contrast, within the other major CBF AML subtype—inv(16) AML—only 1 of 22 patients (4.5%) harbored a ZBTB7A mutation, and no ZBTB7A mutations were detected among patients with CN-AML (n = 50) or non-CBF AML (n = 14)13.

Independent cohorts have confirmed this subtype specificity. In a Japanese study of patients with CBF AML enrolled in the JALSG AML201 trial, ZBTB7A mutations occurred exclusively in the t(8;21) subgroup, accounting for 9.8% (4/41) of cases21. Similarly, integrative multi-omics profiling revealed an enrichment of ZBTB7A mutations among high-risk t(8;21) AML patients exhibiting aberrant leukemic stem and progenitor gene expression signatures22. Furthermore, Lavallée et al. (2016) identified novel somatic ZBTB7A mutations in 15.0% (3/20) of patients with t(8;21) AML, whereas none were observed in inv(16) AML or non-CBF AML control cohorts; notably, patients carrying frameshift ZBTB7A alleles also displayed the lowest ZBTB7A transcript levels23.

Although originally designated as an oncogene in certain solid tumors, ZBTB7A exhibits context-dependent functions as either a tumor promoter or a tumor suppressor depending on tissue lineage. In breast cancer cell lines and clinical tumor specimens, ZBTB7A is frequently overexpressed and promotes cellular migration, invasion, and metastasis via NF-κB-mediated epithelial–mesenchymal transition24,25. Elevated ZBTB7A expression is likewise associated with shorter overall survival in patients with colorectal cancer, where it enhances in vitro cell proliferation and in vivo xenograft tumorigenicity26.

Conversely, compelling evidence establishes ZBTB7A as a bona fide tumor suppressor in endometrial and myeloid malignancies. In uterine corpus endometrial carcinoma (UCEC), downregulation of ZBTB7A accelerates cancer cell proliferation and migration in vitro and correlates with poorer clinical prognosis27. In the hematopoietic compartment, knockdown of ZBTB7A in mononuclear cells derived from healthy mobilized peripheral blood delays terminal erythroid maturation28. Crucially, this erythroid differentiation block cooperates directly with RUNX1::ETO in murine leukemogenesis: Arfelli et al. (2023) reported that conditional ZBTB7A knockout (KO) in RUNX1::ETO-expressing mice resulted in 100% penetrance of acute leukemia29. The spectrum of somatic loss-of-function (LOF) ZBTB7A mutations compiled from the literature and their domain distribution are depicted in Figure 1.

Functionally, WT ZBTB7A counteracts RUNX1::ETO-driven hematopoietic stem and progenitor cell (HSPC) expansion. In human CD34⁺ (hCD34⁺) cells transduced with a C-terminally truncated, leukemogenic isoform of RUNX1::ETO (RUNX1::ETOtr), co-expression of WT ZBTB7A completely abrogated clonal expansion30. By contrast, co-expression of LOF ZBTB7A mutants (ZBTB7A R402C or ZBTB7A A175fs) failed to restrain RUNX1::ETOtr-driven clonal outgrowth. Moreover, ectopic expression of WT ZBTB7A in both the t(8;21)-positive Kasumi-1 cell line and primary hCD34⁺ cells induced cell cycle arrest, increasing the proportion of cells in the G0/G1 phase and reducing the S-phase fraction relative to ZBTB7A-mutant cells30. With respect to myeloid lineage commitment, WT ZBTB7A promotes granulopoiesis while repressing monocytic differentiation. Loss-of-function mutations in ZBTB7A abolish this lineage control and cooperate with RUNX1::ETO to block granulocytic maturation, accompanied by upregulated surface CD14 expression indicative of monocytic skewing30,31.

The experimental designs, studied ZBTB7A variants, and metabolic phenotypes reported across the reviewed literature are detailed in Table 1 and integrated in Figure 1.

In clinical cohorts of t(8;21) AML, somatic mutations in signaling pathway genes—most notably KIT, NRAS, KRAS, FLT3, and JAK2—represent the most frequent co-occurring genetic lesions alongside RUNX1::ETO40,41. Just as RUNX1::ETO requires cooperating mutations to induce overt leukemia2,3, ZBTB7A inactivation likely interacts with co-occurring signaling and epigenetic mutations to orchestrate global metabolic reprogramming in t(8;21) AML. For example, KIT mutations are the most prevalent secondary alterations in both adult and pediatric t(8;21) AML and are strongly associated with higher relapse rates and inferior overall and progression-free survival42,43. Beyond proliferative signaling, aberrant KIT activation promotes glutaminolysis, which depletes microenvironmental glutamine to suppress anti-tumor T-cell proliferation and enhance the immunosuppressive activity of myeloid-derived suppressor cells44. Similarly, recurrent mutations in EZH2, NRAS, TET2, and JAK3 identified in relapsed or refractory RUNX1::RUNX1T1 AML have been linked to distinct alterations in lipid metabolism and glycolytic flux45. Elucidating the combinatorial metabolic effects of ZBTB7A loss alongside co-occurring KIT, RAS, or epigenetic mutations represents a priority for future multi-omics research in t(8;21) AML.

Somatic loss-of-function mutations in ZBTB7A represent a recurrent, subtype-enriched genetic lesion in t(8;21) AML that disrupts the transcriptional repression of key enzymes governing glycolysis and lipid metabolism. By de-repressing glycolytic regulators (SLC2A3, PFKP, and PKM) and upregulating de novo lipogenesis, beta-oxidation, and ketogenesis, ZBTB7A inactivation confers metabolic flexibility and a survival advantage to leukemic stem and progenitor cells within the hypoxic bone marrow microenvironment. Acting in concert with the RUNX1::ETO fusion oncoprotein, loss of ZBTB7A reinforces myeloid differentiation arrest and accelerates clonal expansion. Importantly, this metabolic rewiring creates actionable therapeutic vulnerabilities, rendering ZBTB7A-deficient leukemic cells hypersensitive to pharmacological inhibitors of glycolysis (such as 2-deoxy-D-glucose) and lipid metabolism (such as etomoxir). Targeted inhibition of these dysregulated metabolic nodes holds considerable promise for improving therapeutic outcomes in patients with ZBTB7A-mutant t(8;21) AML.