Human Pathology: Case Reports 20 (2020) 200359 Contents lists available at ScienceDirect Human Pathology: Case Reports journal homepage: www.elsevier.com/locate/ehpc Case Report Novel KMT2A-ATP5L gene fusion in a young adult with rapidly progressive Ph-like t(9;12) acute B lymphoblastic leukemia T ⁎ Cyrus Parsa (D.O.)a,c, , Amanda Thompsonb, Robert Orlando (M.D., Ph.D.)c, Ravin Rupani (M.D.)d, Jin Guo (M.D.)e a Western University of Health Sciences, Department of Pathology, United States b Western University of Health Sciences, MS III, United States c Beverly Hospital, Department of Pathology, United States d Department of Medicine, Hematology/Oncology, United States e Western University of Health Sciences, Department of Pathology, United States ARTICLE INFO ABSTRACT Keywords: Chromosomal abnormalities involving 11q23 with Lysine [K]specific MethylTransferase 2A (KMT2A) gene re- Acute lymphoblastic leukemia arrangement are common among children with aggressive acute leukemias. In KMT2A-rearranged adult Acute t(9;12) Lymphoblastic Leukemia (ALL), five translocation partner genes account for greater than 95% of KMT2A fusion t(11) (q23.3) genes. Rearrangements in the KMT2A gene tend to be associated with poor prognoses. Overexpression of genes KMT2A-ATP5L gene fusion secondary to KMT2A rearrangement contributes to cancer cell survival and growth. The identity of the KMT2A fusion partner gene may also affect the ultimate phenotype of an acute leukemia. We present a case of acute B- lymphoblastic leukemia in a 26-year-old male with a translocation between chromosomes 9 and 12 and novel structural genomic alteration, t(11) (q23.3), resulting in KMT2A-ATP5L gene fusion with dismal prognosis. This structural alteration, not yet reported to our knowledge in the scientific literature, may represent an additional unfavorable prognostic marker in young adults with Philadelphia chromosome (Ph)-like ALL. 1. Introduction transformation through distinct genome architectural routes that are determined by both recombination activating gene (RAG)-dependent Long-term survival of adult patients with ALL less than 60 years old and RAG-independent DNA damage and a block in cell development remains relatively low, 30 to 40%, in spite of improvement in ther- [2]. Rearrangements in the KMT2A gene (previously known as Mixed apeutic regimens, in part attributed to limited availability of molecular Lineage Leukemia 1 or MLL1), occur in approximately 10% of acute prognostic markers. Prognostic markers contributing to patient man- leukemias, and tend to be associated with poor prognoses [3].Asof agement, risk assessment and long-term survival include: age at pre- 2017, 135 different KMT2A gene rearrangements had been identified, sentation; white blood cell count; immunophenotype of blasts; cyto- 35 of which were found recurrently, and 9 of which accounted for genetics; gene fusions; molecular abnormalities; and a more recently greater than 90% of KMT2A recombination cases [4]. In KMT2A-rear- described Ph-like characteristics. The latter is a genetically hetero- ranged adult ALL, 5 translocation partner genes account for greater geneous ALL subtype defined by a gene expression profile similar to the than 95% of KMT2A fusion genes, which include (in order of fre- Ph-positive ALL [1]. The association between gene expression patterns quency): AF4 (also known as AFF1), ENL, AF6, AF9, and AF10 [5]. with recurrent chromosomal translocations in ALL has been helpful in According to Lafage-Pochitaloff et al, out of 617 cases of Philadelphia the development of rapidly expanding field of specific gene markers chromosome negative, B-cell precursor ALL, KMT2A-AFF1 fusion po- and gene expression profiles that provide ongoing prognostic in- sitive cases had worse outcomes than KMT2A fusions with other formation for these patients. translocation partner genes [6]. We present a case of a 26-year-old male Amplification of (11q23) region, has been reported in a subset of with t(9;12) and a novel structural genomic alteration, t(11) (q23.3), human leukemia patients leading to the overexpression of several resulting KMT2A-ATP5L gene fusion with an extremely poor prognosis. cancer genes, including KMT2A. Lymphocytes undergo malignant Structural genomic alteration, t(11) (q23.3), resulting in KMT2A-ATP5L ⁎ Corresponding author. E-mail addresses: [email protected] (C. Parsa), [email protected] (A. Thompson), [email protected] (R. Orlando), [email protected] (R. Rupani), [email protected] (J. Guo). https://doi.org/10.1016/j.ehpc.2020.200359 Received 11 September 2019; Received in revised form 8 December 2019; Accepted 9 December 2019 2214-3300/ © 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). C. Parsa, et al. Human Pathology: Case Reports 20 (2020) 200359 Fig. 1. Peripheral smear with lymphoblasts showing variably indented nuclei Fig. 3. High-power view of bone marrow showing replacement by lympho- and occasional nucleoli. blasts with variable morphologic features. gene fusion has not yet been reported to our knowledge in the scientific morphologically similar to those seen in the peripheral blood (Fig. 3). literature. KMT2A-ATP5L gene fusion may represent an independent Smear preparation of bone marrow aspirate, consisted predominantly prognostic factor or further negatively impact a subset of high risk ALL of immature lymphoid cells with variable morphologic features, in- patients that may benefit from alternative therapeutic approach. cluding some showing faint cytoplasmic granularity suggestive of myeloid lineage (Fig. 4). Immunohistochemical stain for TdT high- lighted presence of abundant lymphoblasts (Fig. 5). A concurrently 2. Case report performed flow cytometry analysis of the bone marrow aspirate, de- tected 78% lymphoblasts positive for the following markers: CD19, fi A 26-year-old male with no signi cant prior medical history pre- CD20, CD10, CD38, HLADR, CD79a, CD22, and TdT. The blasts were sented to the emergency department with severe generalized weakness negative for CD34, T-cell and myeloid antigens. fi of ve days duration. The patient also complained of sore throat, dry Cytogenetic analysis of the bone marrow aspirate showed the fol- cough, dyspnea on exertion, palpitations, headaches, dizziness, and lowing karyotype: “46,XY,der(9)inv(9)(p12q13)t(9;12)(p13;p11.2),der subjective fevers. Laboratory studies included the following complete (12)t(9;12)[12]/46,XY[8]”. This was interpreted as abnormal with 3 3 blood count (CBC): WBC = 41,000/mm , RBC = 4.3million/mm , twelve cells showing a translocation between chromosomes 9 and 12 HGB = 11.9 g/dL, and HCT = 36.7%. The red cell indices were within (Fig. 6) and eight cells showing a normal karyotype. The abnormal 3 ff normal limits and platelet count was 207,000/mm . The WBC di er- chromosome 9 appeared as a complex rearrangement resulting from a ential count consisted of 8% polys, 2% bands, 85% blasts, and 5% pericentric inversion and translocation of the short arm with the short monocytes. The blasts in the peripheral blood smear varied from 14 to arm of chromosome 12. The abnormal chromosome 12 was interpreted ff 20 µm in diameter with variably cleaved large nuclei showing di use as a derivative with material from the short arm of chromosome 9 on chromatin pattern with occasional prominent nucleoli surrounded by scant basophilic cytoplasm (Fig. 1). A subsequently performed bone marrow was 100% cellular (Fig. 2) consisting of abundant blasts, Fig. 4. Smear preparation of bone marrow aspirate, consisting predominantly of immature lymphoid cells similar to those in the peripheral blood smear ac- Fig. 2. Bone marrow biopsy showing marked hypercellularity due to replace- companied by 3 cells showing faint cytoplasmic granularity suggestive of ment of hematopoietic marrow by lymphoblasts. myeloid lineage. 2 C. Parsa, et al. Human Pathology: Case Reports 20 (2020) 200359 diameter in the right external iliac region. Other significant laboratory findings included: Epstein-Barr (EBV) capsid IgG antibody = 227 (negative < 18), EBV nuclear antigen IgG antibody = 360 (negative < 18) suggestive of past EBV infection; positive ANA screen with ANA titer = 1: 80; total bilirubin = 10.9 mg/ dL with 5.5 mg/dL being direct bilirubin; AST = 6747 IU/L, ALT = 5484 IU/L; and serum protein electrophoresis consistent with acute phase reaction. The patient rapidly deteriorated, becoming obtunded and deeply jaundiced with significantly elevated liver function tests including persistent prolonged INR, 5.92 to > 8.00, and died approximately 30 days following the initial presentation at the emergency department. 3. Discussion Philadelphia chromosome positivity and BAALC gene expression [7] are known prognostic markers associated with unfavorable outcome in patients with acute lymphoblastic leukemia. Philadelphia chromosome- like acute lymphoblastic leukemia (Ph-like ALL) is a recently described Fig. 5. Immunohistochemical stain highlights abundant TdT positive blasts. B-cell precursor ALL with a gene expression profile and a high fre- quency of IKZF1 gene alteration similar to that of Ph-positive ALL [1]. Cytogenetically visible abnormalities of the short arm of chromosome 9 are frequent in B-other-ALL [8]. The majority are visible deletions of PAX5. The PAX5 gene encodes a transcription factor, which plays a key role in B-cell commitment and maintenance. The ATP5L gene encodes for mitochondrial ATP synthase subunit gamma, its specific function is not yet known [6]. According to one study, expression of the ATP5L gene was found to be upregulated in samples from breast tumors that highly expressed the oncogene ERBB2 [9]. The clinical significance of ATP5L overexpression, especially with regards to patients with ALL, is not currently known. KMT2A-ATP5L gene fusion with t(9;12) may represent prognostic factors that sig- nificantly negatively impact this subset of high risk ALL patients. In our case presentation, it is unclear how or whether the nature of this spe- cific KMT2A fusion partner, ATP5L, may have contributed to our pa- tient’s rapidly progressive outcome.