Mariana Tavares de Souza

Secondary abnormalities involving 1q or 13q and poor outcome in high stage Burkitt leukemia/lymphoma cases with 8q24 rearrangement at diagnosis

Classical Burkitt lymphoma/leukemia (BL/L) presenting L3 morphology is found in 1% of childhood ALL. Recently, it has been described that secondary abnormalities could influence the prognosis of these patients. However, little information is available on these cytogenetic abnormalities and their prognostic importance in BL/L. Here, we report four new childhood BL/L cases associated with duplication within 1q or 13q, which exhibited a very unfavorable therapeutic response. We performed both classical and molecular cytogenetic analysis by multicolor chromosome banding of the secondary abnormalities involving the long arms of chromosome 1 or 13. These patients were previously treated with BFM-90 protocol. All of them died during or after the initial treatment. Here, for the first time, the exact breakpoints of the derivative chromosomes involved were determined at the cytogenetic level as 1q21 and 13q33 each.

A rare cryptic and complex rearrangement leading to MLL-MLLT10 gene fusion masked by del(10)(p12) in a child with acute monoblastic leukemia (AML-M5)

Acute myeloid leukemia (AML) in young children, defined as hose younger than 24 months of age, occurs in 3–5% of all peditric leukemias. Rearrangements involving the MLL gene, located n the 11q23 region, are between the most common cytogenetic berrations found in M4 or M5 AML subtypes. MLL rearrangement s highly heterogeneous with more than 60 different fusion parters described to date. An association between the type of MLL earrangement and prognosis has been reported [1]. Most of the MLL rearrangements result from simple reciproal translocations. However, rearrangements between MLL and LLT10 gene (also AF10) on chromosome 10p12 frequently result rom complex chromosomal rearrangement. Several types of chroosomal rearrangements involving three or more chromosomal reaks, such as inversions and insertions, have been reported. The atter occurs because MLL is transcribed from centromere to telomre and MLLT10 from telomere to centromere [2]. In some instances the accurate recognition of the t(10;11) via anding cytogenetics methods is difficult. Thus, more sophistiated molecular approaches such as multicolor fluorescence in situ ybridization (FISH), specific RT-PCR, and/or genomic PCR methds are required to uncover these MLL rearrangements, especially nusual, complex, and/or cryptic rearrangements [3,4]. Here, we escribe a rare case of cryptic insertion of chromosome 10 mateial in a derivative chromosome 11 in which the combination of everal molecular approaches was decisive to reveal the nature of complex and cryptic rearrangement leading to the MLL-MLLT10 ene fusion in a child with AML-M5.

Unbalanced chromosome 1 abnormalities leading to partial trisomy 1q in four infants with Down syndrome and acute megakaryocytic leukemia

BackgroundChildren with Down syndrome (DS) have an increased risk of childhood acute leukemia, especially acute megakaryoblastic leukemia (AMKL) also called acute myeloid leukemia (AML) type M7. Here four yet unreported infants with such malignancies are reported.ResultsAn unbalanced translocation involving chromosome 1 was identified by GTG banding in all cases. These were characterized in more detail by molecular cytogenetic approaches. Additional molecular analysis revealed in three of the four cases mutations in exon 2 of the GATA binding protein 1 (globin transcription factor 1), located in Xp11.23.ConclusionOur results corroborate that abnormalities of chromosome 1 are common in DS-associated AMKL. Whether this chromosomal region contains gene(s) involved in hematopoietic malignant transformation remains to be determined.

Conventional and molecular cytogenetic characterization of Burkitt lymphoma with bone marrow involvement in Brazilian children and adolescents.

Burkitt lymphoma/leukemia (BL/L) is cytogenetically characterized by the t(8;14)(q24;q32) or its variants, t(2;8)(p11;q21), and t(8;22)(q24;q11.2), which juxtapose the MYC oncogene to one of the three immunoglobulin loci. The overall cure rate of BL/L in children is 70–90%, but patients diagnosed with advanced‐stage disease have a less favorable prognosis. It is possible that secondary chromosomal abnormalities contribute to this unfavorable prognosis via chemotherapy resistance, but the results of genetic studies have been inconsistent. This study aimed to identify and characterize secondary chromosomal abnormalities associated with the t(8;14) and its variants in children with French‐American‐British‐L3 leukemia or Burkitt lymphoma with bone marrow involvement at the time of diagnosis.

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

BackgroundNear-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.FindingsHerewith, 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.ConclusionWe suggest that p53 is a good target gene to be screened, once p53 is one of the main effectors of cell cycle checkpoints.

A new chromosomal three-way rearrangement involving MLL masked by a t(9;19)(p11;p13) in an infant with acute myeloid leukemia

Infants diagnosed with acute myelogenous leukemia (AML) are likely to have subtypes M4 or M5 characterized by 11q23 abnormalities like a t(9;11)(p22;q23). Detection of all possible types of chromosomal abnormalities, including mixed lineage leukemia (MLL) gene rearrangements at 11q23, is of importance for the identification of biological subgroups, which might differ in drug resistance and/or clinical outcome. Here, we report the clinical, conventional banding and molecular cytogenetics data of a 6-month-old boy with an AML-M5 presenting with a unique cryptic rearrangement involving the MLL gene: a three-way t(9;19;11)(p11.2;p13.1;q23).

A complex karyotype masked a cryptic variant t(8;21)(q22;q22) in a child with acute myeloid leukemia

Cytogenetics Department, Bone Marrow Unit, The National Cancer Institute, Rio de Janeiro, RJ, Brazil, Jena University Hospital, Institute of Human Genetics, Jena, Germany, Stem Cell Department, Bone Marrow Unit, National Cancer Institute, Rio de Janeiro, RJ, Brazil, Pediatric Oncohematology Center, Oswaldo Cruz University Hospital, Recife, PE, Brazil, Service of Pediatric Oncohematology, Lagoa’s Hospital, Rio de Janeiro, RJ, Brazil, and Department of Oncology and International Outreach Program, St. Jude Children’s Research Hospital, Memphis, TN, USA

Molecular cytogenetics studies reveal unexpected chromosomal inversion as variant of t(12;21)(p13;q22) in child with B-cell precursor acute lymphoblastic leukemia

1 Cytogenetics Department and 3 Stem Cells Department, Bone Marrow Unit (CEMO), The National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil, 2 Institute for Human Genetics, Jena University, Jena, Germany, 4 Service of Pediatric Oncohematology, Lagoa ’ s Hospital, Rio de Janeiro, RJ, Brazil and 5 Department of Oncology and International Outreach Program, St. Jude Children ’ s Research Hospital, Memphis, TN, USA

Molecular and Cytogenetic Studies in a Child with Burkitt Lymphoma and Ataxia-Telangiectasia Syndrome Harboring MYC Overexpression and Partial Trisomy 8

Mariana T. De Souza, M.S., Gabriela Vera-Lozada, Ph.D., Moneeb Othman, Ph.D., Teresinha J. Marques-Salles, Ph.D., Luciana W. Pinto, Ph.D., Moisés M. da Rocha, B.S., Soraia Rouxinol, M.D., Thomas Liehr, Ph.D., Raul C. Ribeiro, M.D., Rocio Hassan, Ph.D., and Maria Luiza M. Silva, Ph.D. Cytogenetics Department, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil; Post Graduation Oncology Program, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil; Oncovirology Laboratory, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil; Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, TH, Germany; Department of Genetics, Pernambuco University, Recife, PE, Brazil; Integrated Department of Pathology, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil; Pediatric Hematology Department, Hospital Federal da Lagoa, Rio de Janeiro, RJ, Brazil; Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA; Instituto Pelé Pequeno Príncipe, Postgraduate Program in Child Adolescent Health, Curitiba, Paraná, Brazil

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.