KMT2A-MLLT1 and the Novel SEC16A-KMT2A in a Cryptic 3-Way Translocation t(9;11;19) Present in an Infant With Acute Lymphoblastic Leukemia.

About 25% of the patients with the translocation t(11;19)(q23;p13.3)/KMT2A-MLLT1 present three-way or more complex fusions, associated with a worse prognosis, suggesting that a particular mechanism creates functional KMT2A fusions for this condition. In this work, we show a cryptic three-way translocation t(9;11;19). Interestingly, long-distance inverse polymerase chain reaction sequencing revealed a KMT2A-MLLT1 and the yet unreported out-of-frame SEC16A-KMT2A fusion, associated with low SEC16A expression and KMT2A overexpression, in an infant with B-acute lymphoblastic leukemia presenting a poor prognosis. Our case illustrates the importance of molecular cytogenetic tests in selecting cases for further investigations, which could open perspectives regarding novel therapeutic approaches for poor prognosis childhood leukemias.

An Original Complex Rearrangement Involving Chromosomes 9, 11, and 14, Harboring a Complex KMT2A Gene Rearrangement in an Infant With Mixed-phenotype Acute Leukemia.

KMT2A gene rearrangements represent the most frequent group of abnormalities in childhood leukemia (~70% of cases), with over 120 rearrangements described. The investigation of KMT2A rearrangements is still a vast field to be explored. Several studies have been characterizing different outcomes and leukemogenic mechanisms, depending on the translocation partner gene involved in childhood KMT2A-r leukemias. Therefore, the detection of the translocation partner gene, including in the context of complex rearrangements, may help to better delineate the disease. Here, we describe clinical and molecular cytogenetic data of a new complex variant translocation, involving chromosomes 9, 11, and 14, presenting a KMT2A gene extra copy and rearrangements, in an infant with de novo mixed-phenotype acute leukemia.

A New Complex Karyotype Involving a KMT2A-r Variant Three-Way Translocation in a Rare Clinical Presentation of a Pediatric Patient with Acute Myeloid Leukemia.

Patients with childhood acute myeloid leukemia (AML) with complex karyotypes (CKs) have a dismal outcome. However, for patients with a KMT2A rearrangement (KMT2A-r), the prognosis appears to depend on the fusion partner gene rather than the karyotype structure. Thus, a precise characterization of KMT2A-r and the fusion partner genes, especially in CKs, is of interest for managing AML. We describe the clinical and molecular features of a child who presented with a large abdominal mass, AML, and a new CK, involving chromosomes 11, 16, and 19 leading to a KMT2A-MLLT1 fusion and 2 extra copies of the ELL gene, thus resulting in the concurrent overexpression of MLLT1 and ELL. Molecular cytogenetic studies defined the karyotype as 47,XY,der(11)t(11;16)(q23.3;p11.2),der(16)t(16;19)(p11.2;p13.3),der(19)t(11;19)(q23.3;p13.3),+der(19)t(16;19)(16pter→p11.2::19p13.3→19q11::19p11→19p13.3::16p11.2→16pter). Array CGH revealed a gain of 30.5 Mb in the 16p13.3p11.2 region and a gain of 18.1 Mb in the 19p13.3p12 region. LDI-PCR demonstrated the KMT2A-MLLT1 fusion. Reverse sequence analysis showed that the MLLT1 gene was fused to the 16p11.2 region. RT-qPCR quantification revealed that ELL and MLLT1 were overexpressed (4- and 10-fold, respectively). In summary, this is a pediatric case of AML presenting a novel complex t(11;16;19) variant with overexpression of ELL and MLLT1.

Molecular approaches identify a cryptic MECOM rearrangement in a child with a rapidly progressive myeloid neoplasm.

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.

Altered neutrophil immunophenotypes in childhood B­cell precursor acute lymphoblastic leukemia.

An increasing number of evidences suggest a genetic predisposition in acute lymphoblastic leukemia (ALL) that might favor the occurrence of the driver genetic alterations. Such genetic background might also translate into phenotypic alterations of residual hematopoietic cells. Whether such phenotypic alterations are present in bone marrow (BM) cells from childhood B-cell precursor (BCP)-ALL remains to be investigated. Here we analyzed the immunophenotypic profile of BM and peripheral blood (PB) maturing/matured neutrophils from 118 children with BCP-ALL and their relationship with the features of the disease. Our results showed altered neutrophil phenotypes in most (77%) BCP-ALL cases. The most frequently altered marker was CD10 (53%), followed by CD33 (34%), CD13 (15%), CD15/CD65 (10%) and CD123 (7%). Of note, patients with altered neutrophil phenotypes had younger age (p = 0.03) and lower percentages of BM maturing neutrophils (p = 0.004) together with greater BM lymphocyte (p = 0.04), and mature B-cell (p = 0.03) counts. No significant association was found between an altered neutrophil phenotype and other disease features. These findings point out the potential existence of an altered residual hematopoiesis in most childhood BCP-ALL cases.

An unusual T-cell childhood acute lymphoblastic leukemia harboring a yet unreported near-tetraploid karyotype.

BACKGROUND: Near-tetraploid (model #81-103) and near-triploid (model #67-81) karyotypes are found in around 1% of childhood acute lymphoblastic leukemia. Due to its rarity, these two cytogenetic subgroups are generally included in the hyperdiploid group (model # > 51). Therefore separate informations about these two subgroups are limited to a few reports. Some studies found that near-tetraploidy is relatively more frequent in higher median ages and it is associated to Frech-American-British Classification subtype L2. Although the mechanisms by which leukemic blast cells divide is still unclear, studies have suggested that hyperdiploidy, near-triploidy and near-tetraploidy do not seem to share the same mechanism. FINDINGS: Herewith, we present a new childhood T-acute lymphoblastic leukemia case of near-tetraploid karyotype with loss of two p53-gene copies, characterized in detail by cytogenetic and molecular studies. CONCLUSION: We suggest that p53 is a good target gene to be screened, once p53 is one of the main effectors of cell cycle checkpoints.

Cytogenetic study of 50 Brazilian patients with primary myelodysplastic syndrome

Neste trabalho foram estudados citogeneticamente 50 pacientes de diversas unidades hospitalares do Rio de Janeiro, Brasil, diagnosticados com síndrome mielodisplásica primária. Os dados obtidos mostraram uma freqüência de anomalias cromossômicas de 32 por cento nestes pacientes, sendo as anomalias mais encontradas a del(5q) (10 por cento), -7 (6 por cento) e +8 (quatro por cento). Pacientes com anemia refratária ou anemia refratária com sideroblastos em anel apresentaram cariótipos normais ou com deleçöes simples como del(5q) ou -Y, enquanto pacientes com anemia refratária com excesso de blastos, anemia refratária com excesso de blastos em transformaçäo e leucemia mielomonocítica crônica apresentaram cariótipos complexos ou com anomalias simples do tipo monossomia do 7 ou trissomia do 8, tendo um alto índice de evoluçäo para leucemia mielóide aguda.