Molecular characterization of V(D)J rearrangements in immature acute leukemias.

Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL), T-Lymphoid/Myeloid Mixed Phenotype Acute Leukemia (T/M-MPAL), and Acute Myeloid Leukemia with minimal differentiation (AML-M0) are immature acute leukemias (AL) that present overlapping T-cell lymphoid and myeloid features at different degrees, with impact to disease classification. An interesting strategy to assess lymphoid lineage commitment and maturation is the analysis of V(D)J gene segment recombination, which can be applied to investigate leukemic cells in immature AL. Herein, we revisited 19 ETP-ALL, 8 T/M-MPAL, and 12 AML-M0 pediatric patients to characterize V(D)J rearrangement (V(D)J-r) profiles associated with other somatic alterations.

Interaction between birth characteristics and variants in the childhood lymphoblastic leukemia risk.

Background: The incidence rate of childhood acute lymphoblastic leukemia (ALL) differs worldwide, and the interplay between hemostasis actors and the maladaptive responses to environmental exposures has been explored. It has been proposed that endogenous cortisol, induced by different triggers, would eliminate pre-leukemic clones originated . Herein, we tested if the interaction between , and (players in glucocorticoid secretion) and birth characteristics would be associated with ALL risk.

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia.

Identifying childhood leukemia with an excess of hematological malignancies in first-degree relatives in Brazil.

Background: Familial aggregation in childhood leukemia is associated with epidemiological and genomic factors. Albeit epidemiological studies on the familial history of hematological malignancies (FHHMs) are scarce, genome-wide studies have identified inherited gene variants associated with leukemia risk. We revisited a dataset of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients to explore the familial aggregation of malignancies among their relatives.

A Novel Constitutional t(3;8)(p26;q21) and and Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications.

Background: Childhood myelodysplastic neoplasm (cMDS) often raises concerns about an underlying germline predisposition, and its verification is necessary to guide therapeutic choice and allow family counseling. Here, we report a novel constitutional t(3;8)(p26;q21) in a child with MDS, inherited from the father, the and variants from the maternal origin, and the acquisition of molecular alterations during MDS evolution.

Case Presentation: A 4-year-old girl showed repeated infections and severe neutropenia.

The Interplay of Cesarean-Section Delivery and First-Birth Order as Risk Factors in Acute Lymphoblastic Leukemia.

Background: Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been associated with early-life exposures, including birth by cesarean section (C-section), and a deficit of social exposure (first child). These exposures as proxies for microbiome acquisition in infancy are essential to prime the immune system and restrain later dysregulated immune responses that can trigger ALL in susceptible individuals. We tested risk factors pertaining to immune stimulation that may impact BCP-ALL development.

Multiparametric flow cytometry directing the evaluation of CRLF2 rearrangements and JAK2 status in pediatric B cell precursor acute lymphoblastic leukemia.

Introduction: This study aimed to determine whether cytokine receptor-like factor 2 (CRLF2) antigen expression evaluated using multiparametric flow cytometry (MFC) could predict the genotype of CRLF2 and Janus kinase 2 (JAK2) status for application in the diagnosis of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Methods: A total of 321 BCP-ALL bone marrow samples were collected, 291 at diagnosis and 13 at first relapse, while 17 samples were excluded due to low cellular viability. The CRLF2 antigen expression was evaluated using flow cytometry (percentage of positivity and median fluorescence intensity [MFI]).

GATA2 variants in patients with non-tuberculous mycobacterial or fungal infections without known immunodeficiencies.

Introduction: Haploinsufficiency of the hematopoietic transcription factor GATA2 is associated with a broad spectrum of diseases, including infection susceptibility and neoplasms. We aimed to investigate GATA2 variants in patients with non-tuberculous mycobacterial (NTM) and/or fungal infections (FI) without known immunodeficiencies.

Method: We performed GATA2 genotyping in patients with NTM and/or FI.

The genomic landscape of teenage and young adult T-cell acute lymphoblastic leukemia.

Background: Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T-cell acute lymphoblastic leukemia (T-ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T-ALL has a specific biological-molecular profile distinct from pediatric or adult T-ALL.

Therapy-related acute myeloid leukemia with KMT2A-SNX9 gene fusion associated with a hyperdiploid karyotype after hemophagocytic lymphohistiocytosis.

Therapy-related acute myeloid leukemia (t-AML) following treatment with topoisomerase-II inhibitors has been increasingly reported. These compounds (e.g.

Pediatric Acute Promyelocytic Leukemia: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome.

Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among the geographic regions with relatively higher percentages in the Latin American population. We aimed to explore the population burden of pediatric APL, gathering information from the population-based cancer registry (PBCR) and the diagnosis of APL obtained through incident cases from a hospital-based cohort. The homozygous deletion in glutathione S-transferases (GSTs) leads to a loss of enzyme detoxification activity, possibly affecting the treatment response.

Corrigendum: The Profile of Immunophenotype and Genotype Aberrations in Subsets of Pediatric T-Cell Acute Lymphoblastic Leukemia.

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XRCC4 rs28360071 intronic variant is associated with increased risk for infant acute lymphoblastic leukemia with KMT2A rearrangements.

Early age acute leukemia (EAL) shows a high frequency of KMT2A-rearrangements (KMT2A-r). Previous investigations highlighted double-strand breaks arising from maternal exposure to xenobiotics during pregnancy as a risk factor for EAL and KMT2A-r. In this case-control study, we investigated the relationship between EAL and genetic variants of the nonhomologous end-joining (XRCC6 rs5751129, XRCC4 rs6869366 and rs28360071), since they might affect DNA repair capacity, leading to KMT2A-r and leukemogenesis.

The multiple ways Wnt signaling contributes to acute leukemia pathogenesis.

WNT proteins constitute a very conserved family of secreted glycoproteins that act as short-range ligands for signaling with critical roles in hematopoiesis, embryonic development, and tissue homeostasis. These proteins transduce signals via the canonical pathway, which is β-catenin-mediated and better-characterized, or via more diverse noncanonical pathways that are β-catenin independent and comprise the planar cell polarity (PCP) pathway and the WNT/Ca pathways. Several proteins regulate Wnt signaling through a variety of sophisticated mechanisms.

Age-, sex- and disease subtype-related foetal growth differentials in childhood acute myeloid leukaemia risk: A Childhood Leukemia International Consortium analysis.

Aim: Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases.

MTHFR rs1801133 polymorphism is associated with increased risk of B-cell precursor lymphoblastic leukaemia with recurrent genetic aberrations of fetal origin.

Background: Childhood acute lymphoblastic leukaemia (ALL) is a heterogeneous disease associated with multiple risk factors including genetic susceptibility. Polymorphisms in folate genes have been associated with a protective effect against ALL, although some studies contradict these findings. We aimed to test whether there is an association between the MTHFR rs1801133 variant and the occurrence of B-cell precursor ALL (BCP-ALL) taking in account molecularly distinct subtypes of fetal origin.

Incidence and mortality of myeloid malignancies in children, adolescents and Young adults in Brazil: A population-based study.

Background: Myeloid malignancies (MM) are heterogeneous when it comes to incidence rates and pathogenesis. These variation rates are important to generate hypotheses on causal aetiology. This study aimed to describe incidence and mortality patterns of MM among children, adolescents and young adults (cAYA) in Brazil and to evaluate trends in incidence and mortality rate overtime.

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.

The Profile of Immunophenotype and Genotype Aberrations in Subsets of Pediatric T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a biologically heterogeneous malignancy, which reflects distinctive stages of T-cell differentiation arrest. We have revisited a cohort of pediatric T-ALL, in order to test if immunophenotypes associated with molecular alterations would predict the patient's outcome. Genetic mutations, translocations and copy number alterations were identified through Sanger sequencing, RT-PCR, FISH and multiplex ligation-dependent probe amplification (MLPA).