Citation: Gudipati, M.; Butler, M.; Koka, R.; Baer, M.R.; Ning, Y. Fusion Gene-Based Classification of Variant Cytogenetic Rearrangements in Acute Myeloid Leukemia. Genes 2023, 14, 396. https://doi.org/10.3390/ genes14020396 Academic Editors: Jingwei Yu and Darren Griffin Received: 20 December 2022 Revised: 29 January 2023 Accepted: 1 February 2023 Published: 3 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). genes G C A T T A C G G C A T Communication Fusion Gene-Based Classification of Variant Cytogenetic Rearrangements in Acute Myeloid Leukemia Mary Gudipati 1 , Melody Butler 1 , Rima Koka 1 , Maria R. Baer 2 and Yi Ning 1, * 1 Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA 2 Department of Medicine, University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA * Correspondence: yning@som.umaryland.edu Abstract: Acute myeloid leukemia (AML) represents a heterogeneous disease entity that is continu- ously moving to a more genetically defined classification. The classification of AML with recurrent chromosomal translocations, including those involving core binding factor subunits, plays a critical role in diagnosis, prognosis, treatment stratification, and residual disease evaluation. Accurate classification of variant cytogenetic rearrangements in AML contributes to effective clinical manage- ment. We report here the identification of four variant t(8;V;21) translocations in newly diagnosed AML patients. Two patients showed a t(8;14) and a t(8;10) variation, respectively, with a morpho- logically normal-appearing chromosome 21 in each initial karyotype. Subsequent fluorescence in situ hybridization (FISH) on metaphase cells revealed cryptic three-way translocations t(8;14;21) and t(8;10;21). Each resulted in RUNX1::RUNX1T1 fusion. The other two patients showed kary- otypically visible three-way translocations t(8;16;21) and t(8;20;21), respectively. Each resulted in RUNX1::RUNX1T1 fusion. Our findings demonstrate the importance of recognizing variant forms of t(8;21) translocations and emphasize the value of applying RUNX1::RUNX1T1 FISH for the detection of cryptic and complex rearrangements when abnormalities involving chromosome band 8q22 are observed in patients with AML. Keywords: RUNX1::RUNX1T1 fusion; cryptic translocation; complex rearrangement; acute myeloid leukemia 1. Introduction Acute myeloid leukemia (AML) is a clonal hematopoietic disorder resulting from genetic alterations in normal hematopoietic stem cells. These alterations disrupt normal differentiation and/or cause excessive proliferation of abnormal immature leukemic cells. The classification of AML has shifted from a morphology-based classification to a classi- fication algorithm based primarily on genetic abnormalities. The current World Health Organization (WHO) classification includes a major entity termed AML with recurrent genetic abnormalities, meaning with specific chromosomal or mutational alterations [1–3]. Translocation t(8;21)(q22;q22) is a recurrent cytogenetic abnormality and is one of the most common subtypes of AML, occurring in approximately 5% of AML patients. This subtype has predominantly neutrophilic maturation and is associated with a high rate of complete remission and favorable long-term outcomes [1–6]. The t(8;21) translocation leads to the formation of an oncogenic fusion of RUNX1 (runt-related transcription factor 1) on 21q22 to RUNX1T1 (runt-related transcription factor 1; translocated to 1) on 8q22. The fusion resides on the derivative 8q22. It leads to the disruption of the normal function of the core-binding factor in hematopoietic differentiation and maturation and recruits tran- scriptional repressors to block the expression of genes involved in normal hematopoiesis, thus impairing apoptosis [6]. Genes 2023, 14, 396. https://doi.org/10.3390/genes14020396 https://www.mdpi.com/journal/genes