Co-existence of :: Fusion and Variant in a Pediatric Case with Acute Myeloid Leukemia: a Case Report and Literature Review

Overview

Journal Front Oncol

Specialty Oncology

Date 2023 Dec 28

PMID 38152368

Authors

Liang Wang

Fangzhou Qiu

Yongming Shen

Sen Chen

Ping Si

Affiliations

Soon will be listed here.

Abstract

The lysine(K)-specific methyltransferase 2A gene (), previously known as mixed lineage leukemia (), frequently rearranged in acute leukemia, belongs to one of the most promiscuous genes and has been found fused to more than 80 different partners. :: fusion is a relatively uncommon rearrangement observed in pediatric acute myeloid leukemia (AML) patients, some of which may harbor other mutations. We herein report a case of AML-M4-infant with :: fusion and variant. The 8-month-old girl presented with leukocytosis, anemia and thrombocytopenia. A bone marrow smear disclosed that 64% of the total nucleated cells were blasts. Karyotype analysis showed 46,X,t(X;11)(q24;q23)[10]/46,XX[10]. Fluorescence hybridization analysis suggested a possible break in the gene. After whole transcriptome sequencing, Exon 9 of was fused in-frame with Exon 2 of . This is a typical type of chromosomal rearrangement leading to the :: fusion. Meanwhile, variant [c.2065C>T, p.R689X, variant allele frequency (VAF): 39.8%] was identified. :: fusion has been associated with the pathogenesis of AML, whereas variants are relatively rare genetic events in pediatric AML. Regrettably, the relatives disagreed with the combination chemotherapy, and the patient eventually died of progressive disease. In conclusion, our findings provide a foundation for a better understanding of the genotypic profile of :: associated AML, and the co-existence of :: and variant might contribute to the disease progression and transformation of AML.

References

Borkovskaia A, Bogacheva S, Konyukhova T, Dadakhanova E, Gaskova M, Soldatkina O . Molecular Heterogeneity of Pediatric AML with Atypical Promyelocytes Accumulation in Children-A Single Center Experience. Genes (Basel). 2023; 14(3). PMC: 10048084. DOI: 10.3390/genes14030675. View

Chebly A, Djambas Khayat C, Yammine T, Korban R, Semaan W, Bou Zeid J . Pediatric M5 acute myeloid leukemia with fusion and a favorable outcome. Leuk Res Rep. 2021; 16:100277. PMC: 8566899. DOI: 10.1016/j.lrr.2021.100277. View

Robinson S, Oliver A, Chevassut T, Newbury S . The 3' to 5' Exoribonuclease DIS3: From Structure and Mechanisms to Biological Functions and Role in Human Disease. Biomolecules. 2015; 5(3):1515-39. PMC: 4598762. DOI: 10.3390/biom5031515. View

Ono R, Nakajima H, Ozaki K, Kumagai H, Kawashima T, Taki T . Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J Clin Invest. 2005; 115(4):919-29. PMC: 1062890. DOI: 10.1172/JCI22725. View

Jo A, Tsukimoto I, Ishii E, Asou N, Mitani S, Shimada A . Age-associated difference in gene expression of paediatric acute myelomonocytic lineage leukaemia (FAB M4 and M5 subtypes) and its correlation with prognosis. Br J Haematol. 2009; 144(6):917-29. DOI: 10.1111/j.1365-2141.2008.07531.x. View

Cerveira N, Micci F, Santos J, Pinheiro M, Correia C, Lisboa S . Molecular characterization of the MLL-SEPT6 fusion gene in acute myeloid leukemia: identification of novel fusion transcripts and cloning of genomic breakpoint junctions. Haematologica. 2008; 93(7):1076-80. DOI: 10.3324/haematol.12594. View

Meyer C, Larghero P, Almeida Lopes B, Burmeister T, Groger D, Sutton R . The KMT2A recombinome of acute leukemias in 2023. Leukemia. 2023; 37(5):988-1005. PMC: 10169636. DOI: 10.1038/s41375-023-01877-1. View

Kim H, Ki C, Park Q, Koo H, Yoo K, Kim E . MLL/SEPTIN6 chimeric transcript from inv ins(X;11)(q24;q23q13) in acute monocytic leukemia: report of a case and review of the literature. Genes Chromosomes Cancer. 2003; 38(1):8-12. DOI: 10.1002/gcc.10235. View

Li M, Datto M, Duncavage E, Kulkarni S, Lindeman N, Roy S . Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2016; 19(1):4-23. PMC: 5707196. DOI: 10.1016/j.jmoldx.2016.10.002. View

10.

Shih L, Liang D, Fu J, Wu J, Wang P, Lin T . Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement. Leukemia. 2005; 20(2):218-23. DOI: 10.1038/sj.leu.2404024. View

11.

Cerveira N, Lisboa S, Correia C, Bizarro S, Santos J, Torres L . Genetic and clinical characterization of 45 acute leukemia patients with MLL gene rearrangements from a single institution. Mol Oncol. 2012; 6(5):553-64. PMC: 5528393. DOI: 10.1016/j.molonc.2012.06.004. View

12.

Santos J, Cerveira N, Bizarro S, Ribeiro F, Correia C, Torres L . Expression pattern of the septin gene family in acute myeloid leukemias with and without MLL-SEPT fusion genes. Leuk Res. 2009; 34(5):615-21. DOI: 10.1016/j.leukres.2009.08.018. View

13.

Ono R, Taki T, Taketani T, Kawaguchi H, Taniwaki M, Okamura T . SEPTIN6, a human homologue to mouse Septin6, is fused to MLL in infant acute myeloid leukemia with complex chromosomal abnormalities involving 11q23 and Xq24. Cancer Res. 2002; 62(2):333-7. View

14.

Daser A, Rabbitts T . The versatile mixed lineage leukaemia gene MLL and its many associations in leukaemogenesis. Semin Cancer Biol. 2005; 15(3):175-88. DOI: 10.1016/j.semcancer.2005.01.007. View

15.

Nakata Y, Mori T, Yamazaki T, Suzuki T, Okazaki T, Kurosawa Y . Acute myeloid leukemia with hypergranular cytoplasm accompanied by t(X;11)(q24;q23) and rearrangement of the MLL gene. Leuk Res. 1999; 23(1):85-8. DOI: 10.1016/s0145-2126(98)00131-3. View

16.

Todoerti K, Ronchetti D, Favasuli V, Maura F, Morabito F, Bolli N . DIS3 mutations in multiple myeloma impact the transcriptional signature and clinical outcome. Haematologica. 2021; 107(4):921-932. PMC: 8968896. DOI: 10.3324/haematol.2021.278342. View

17.

Welch J, Ley T, Link D, Miller C, Larson D, Koboldt D . The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012; 150(2):264-78. PMC: 3407563. DOI: 10.1016/j.cell.2012.06.023. View

18.

Strehl S, Konig M, Meyer C, Schneider B, Harbott J, Jager U . Molecular dissection of t(11;17) in acute myeloid leukemia reveals a variety of gene fusions with heterogeneous fusion transcripts and multiple splice variants. Genes Chromosomes Cancer. 2006; 45(11):1041-9. DOI: 10.1002/gcc.20372. View

19.

Kadkol S, Bruno A, Oh S, Schmidt M, Lindgren V . MLL-SEPT6 fusion transcript with a novel sequence in an infant with acute myeloid leukemia. Cancer Genet Cytogenet. 2006; 168(2):162-7. DOI: 10.1016/j.cancergencyto.2006.02.020. View

20.

Chen F, Yang Y, Fu S . Clinical profile in positive acute myeloid leukemia: Does it often co-occur with mutations?. Front Med (Lausanne). 2022; 9:890959. PMC: 9532577. DOI: 10.3389/fmed.2022.890959. View