Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene (KMT2A, also known as MLL). Specific KMT2A fusion partners are associated with the disease phenotype (lymphoblastic vs. myeloid), and the type of KMT2A rearrangement also has prognostic implications. However, the KMT2A partner gene cannot always be identified by banding karyotyping. We sought to identify such partner genes in 13 cases of childhood leukemia with uninformative karyotypes by combining molecular techniques, including multicolor banding FISH, reverse-transcriptase PCR, and long-distance inverse PCR. Of the KMT2A fusion partner genes, MLLT3 was present in five patients, all with acute lymphoblastic leukemia, MLLT1 in two patients, and MLLT10, MLLT4, MLLT11, and AFF1 in one patient each. Reciprocal reading by long-distance inverse PCR also disclosed KMT2A fusions with PITPNA in one patient, with LOC100132273 in another patient, and with DNA sequences not compatible with any gene in three patients. The most common KMT2A breakpoint region was intron/exon 9 (3/8 patients), followed by intron/exon 11 and 10. Finally, multicolor banding revealed breakpoints in other chromosomes whose biological and prognostic implications remain to be determined. We conclude that the combination of molecular techniques used in this study can efficiently identify KMT2A fusion partners in complex pediatric acute leukemia karyotypes. Copyright © 2016 John Wiley & Sons, Ltd.
Myeloid malignancies can be either primary or secondary, whether or not a specific cause can be determined. Fanconi anemia (FA), a rare constitutional bone marrow failure, usually presents an increased possibility of clonal evolution, due to the increase in chromosomal instability, TP53 activation, and cell death. The evolution of FA may include aplastic anemia by the progressive failure of the bone marrow and myelod neoplasias, such as acute myeloid leukemia and myelodysplastic syndrome. Chromosome abnormalities, particularly of chromosomes, 1, 3, and 7, during the aplastic phase of the disease are predictive of evolution to acute myeloid leukemia/myelodysplastic syndrome. Cytogenetic studies are indispensable to characterize chromosome abnormalities, and thus an important part of the clinical management, and for planning of therapeutic interventions. Here, clinical data and outcomes of 4 FA, 3 of them with myeloid malignances and 1 asymptomatic, and detailed characterization of their chromosome abnormalities using cytogenetics techniques are described.
Myeloid neoplasms are a heterogeneous group of hematologic disorders with divergent patterns of cell differentiation and proliferation, as well as divergent clinical courses. Rare recurrent genetic abnormalities related to this group of cancers are associated with poor outcomes. One such abnormality is the MECOM gene rearrangement that typically occurs in cases with chromosome 7 abnormalities. MECOM encodes a transcription factor that plays an essential role in cell proliferation and maintenance and also in epigenetic regulation. Aberrant expression of this gene is associated with reduced survival. Hence, its detailed characterization provides biological and clinical information relevant to the management of pediatric myeloid neoplasms. In this work, we describe a rare karyotype harboring three copies of MECOM with overexpression of the gene in a child with a very aggressive myeloid neoplasm. Cytogenetic studies defined the karyotype as 46,XX,der(7)t(3;7)(q26.2;q21.2). Array comparative genomic hybridization (aCGH) revealed a gain of 26.04 Mb in the 3q26.2-3qter region and a loss of 66.6 Mb in the 7q21.2-7qter region. RT-qPCR analysis detected elevated expression of the MECOM and CDK6 genes (458.5-fold and 35.2-fold, respectively). Overall, we show the importance of performing detailed molecular cytogenetic analysis of MECOM to enable appropriate management of high-risk pediatric myeloid neoplasms.
The ETV6/RUNX1 (TEL/AML1) gene fusion is the most common gene rearrangement in childhood B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) that occurs in 19-27% of cases [1]. This gene fusion is caused by the t(12;21)(p13;q22) mutation, which results in a chimeric protein that acts as a trans-dominant repressor of RUNX1-regulated target genes [2]. This translocation usually escapes banding cytogenetics, and molecular techniques such as reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) are useful for its detection [3]. Several studies have shown that ETV6/RUNX1 confers a favorable prognosis in childhood ALL [1]. However, other investigators have shown incidence of the ETV6/RUNX1 in relapsed ALL [4][5][6]. In addition, most cases of childhood BCP-ALL with the ETV6/RUNX1 fusion relapse late. Features of ETV6/RUNX1 associated with poor prognosis include two copies of the fusion signal, loss of second ETV6 signal and loss of the second RUNX1 or extra signal, near-tetraploid modal number, or a complex karyotype [7]. As cases of BCP-ALL often show poor chromosome morphology, assessing the molecular heterogeneity of ALL cases with the ETV6/RUNX1 fusion requires highly sensitive methods, such as FISHbanding [8].In the present report, we describe banding and molecular cytogenetic analyses of a childhood BCP-ALL case with t(12;21) harboring a novel three-way molecular variant involving chromosome 11.The patient is a 13-year-old girl admitted to the Hematology Service in Clementino Fraga Filho University Hospital (HUCCF), Rio de Janeiro. On admission, she presented a history of two months of joint pain in the legs, spine (thoracolumbar), right knee, and left shoulder. These symptoms progressed, with fever, epistaxis, and petechial rash in shoulder and legs. Physical examination showed remarkable hepatomegaly (the liver was 10 cm below the right costal margin) and splenomegaly (the spleen was 6 cm below the left costal margin). White blood cell (WBC) count was 26.7 9 10 9 /L, and platelet count was 18 9 10 9 /L. Morphologic evaluation of bone marrow contents showed hypercellularity with 80% blast cells and lymphoid characteristics. Flow cytometry analysis revealed blasts that expressed CD19, CD10, CD20, cIgM, CD79a, and HLA-DR. Immunohistochemistry analysis revealed 80% of Ki-67 expression. The final diagnosis was BCP-ALL. RT-PCR analysis revealed the ETV6/RUNX1 fusion. The patient was treated according to the hyper-CVAD protocol [9], which resulted in complete remission achieved on day 15 of the treatment. The patient has remained in remission for more than 10 months. Cytogenetic G-banding studies at the time of D. R
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