Search Results (32)

Background/Objective: Radiotherapy for leukemia, the most common childhood malignancy, often exposes patients to radiation, increasing the risk of second malignancies, including thyroid cancer. To assess the incidence and survival outcomes of thyroid cancer after childhood acute lymphoblastic leukemia (ALL). Methods: We systematically reviewed articles reporting the incidence of thyroid cancer in childhood leukemia survivors (age at diagnosis < 18 years) published between 2000–2024 in Science Direct, PubMed, Google Scholar, CENTRAL, and EMBASE. The Newcastle Ottawa Scale was utilized to appraise the methodological quality of the included studies. Descriptive statistics and calculations of incidence were performed using Microsoft Excel. Results: The literature search yielded 1265 articles, of which 18 met the inclusion criteria. Data from 135,861 childhood cancer survivors, among whom 102,070 had a confirmed diagnosis of childhood leukemia, including ALL. The crude incidence of secondary malignancies after childhood leukemia was 10.1 per 1000 patients. Among these, 1.5 per 1000 patients developed second thyroid carcinomas. Overall, 14.6% of the second malignancies in childhood leukemia survivors were thyroid carcinomas, mostly of the papillary type. Survival rates after second thyroid cancer were 100% in all 11/18 studies reporting this outcome. Radiotherapy had been used as part of ALL treatments in 17/18 studies. The use of radiotherapy, female sex, and younger age at the diagnosis of primary ALL emerged as important risk factors for thyroid cancer. Conclusions: Thyroid carcinomas account for ~15% of secondary malignancies after childhood leukemia, with radiation remaining a significant risk factor despite its overall reduced use for the treatment of ALL in the last few decades. Importantly, survival rates remain high. Further research is warranted to determine the incidence and outcomes of thyroid cancer in childhood ALL survivors Full article

ETV6::RUNX1-positive pediatric acute lymphoblastic leukemia frequently has a prenatal origin and follows a two-hit model: a first somatic alteration leads to the formation of the oncogenic fusion gene ETV6::RUNX1 and the generation of a preleukemic clone in utero. Secondary hits after birth are necessary to convert the preleukemic clone into clinically overt leukemia. However, prenatal factors triggering the first hit have not yet been determined. Here, we explore the influence of maternal factors during pregnancy on the prevalence of the ETV6::RUNX1 fusion. To this end, we employed a nested interventional cohort study (IMPACT-BCN trial), including 1221 pregnancies (randomized into usual care, a Mediterranean diet, or mindfulness-based stress reduction) and determined the prevalence of the fusion gene in the DNA of cord blood samples at delivery (n = 741) using the state-of-the-art GIPFEL (genomic inverse PCR for exploration of ligated breakpoints) technique. A total of 6.5% (n = 48 of 741) of healthy newborns tested positive for ETV6::RUNX1. Our multiple regression analyses showed a trend toward lower ETV6::RUNX1 prevalence in offspring of the high-adherence intervention groups. Strikingly, corticosteroid use for lung maturation during pregnancy was significantly associated with ETV6::RUNX1 (adjusted OR 3.9, 95% CI 1.6–9.8) in 39 neonates, particularly if applied before 26 weeks of gestation (OR 7.7, 95% CI 1.08–50) or if betamethasone (OR 4.0, 95% CI 1.4–11.3) was used. Prenatal exposure to corticosteroids within a critical time window may therefore increase the risk of developing ETV6::RUNX1+ preleukemic clones and potentially leukemia after birth. Taken together, this study indicates that ETV6::RUNX1 preleukemia prevalence may be modulated and potentially prevented. Full article

Recent studies have demonstrated the association between constitutional ring chromosome 21 (r(21)c) and the development of B-cell acute lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21). iAMP21 acts as a driver which is often accompanied by secondary alterations that influence disease progression. Here, we report an atypical case of iAMP21 B-ALL with a unique molecular profile in the context of r(21)c. The onset of B-ALL occurred significantly earlier than previously reported in iAMP21-ALL, likely due to the presence of r(21)c. Only scarce cases of iAMP21 with concomitant PAX5 fusions have been reported. Through an extensive genomic characterization, the novel WWOX::PAX5 as well as 13q12.2 deletion involving FLT3 overexpression was found. These findings suggest that r(21)c may induce chromosomal instability on chromosome 21, triggering chromothripsis and leading to iAMP21-ALL. This case provides valuable insights to unravel the complex interplay between germline and somatic genetic alterations in leukemia. Moreover, it underscores the need for thorough genetic evaluation and multidisciplinary management in patients with syndromic presentation, particularly when rare genetic events may contribute to hematologic malignancies. Full article

Genomic instability is one of the main drivers of tumorigenesis and the development of hematological malignancies. Cancer cells can remedy chemotherapeutic-induced DNA damage by upregulating DNA-repair genes and ultimately inducing therapy resistance. Nevertheless, the association between the DNA-repair genes, drug resistance, and disease relapse has not been well characterized in acute lymphoblastic leukemia (ALL). This study aimed to explore the role of the DNA-repair machinery and the molecular mechanisms by which it is regulated in early- and late-relapsing pediatric ALL patients. We performed secondary data analysis on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)—ALL expansion phase II trial of 198 relapsed pediatric precursor B-cell ALL. Comprehensive genetic and epigenetic investigations of 147 DNA-repair genes were conducted in the study. Gene expression was assessed using Microarray and RNA-sequencing platforms. Genomic alternations, methylation status, and miRNA transcriptome were investigated for the candidate DNA-repair genes. We identified three DNA-repair genes, ALKBH3, NHEJ1, and PARP1, that were upregulated in early relapsers compared to late relapsers (p < 0.05). Such upregulation at diagnosis was significantly associated with disease-free survival and overall survival in precursor-B-ALL (p < 0.05). Moreover, PARP1 upregulation accompanied a significant downregulation of its targeting miRNA, miR-1301-3p (p = 0.0152), which was strongly linked with poorer disease-free and overall survivals. Upregulation of DNA-repair genes, PARP1 in particular, increases the likelihood of early relapse of precursor-B-ALL in children. The observation that PARP1 was upregulated in early relapsers relative to late relapsers might serve as a valid rationale for proposing alternative treatment approaches, such as using PARP inhibitors with chemotherapy. Full article

Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic insufficiency. The mechanisms by which clonal malignant cells inhibit normal hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) have not been unraveled so far. Given the pivotal role of mesenchymal stromal cells (MSCs) in the regulation of hematopoiesis in the BM niche it is assumed that MSCs also play a relevant role in the pathogenesis of hematological neoplasms. We aimed to identify overlapping mechanisms in MSCs derived from myeloid and lymphoid neoplasms contributing to disease progression and suppression of HSPCs to develop interventions that target these mechanisms. MSCs derived from healthy donors (n = 44) and patients diagnosed with myeloproliferative neoplasia (n = 11), myelodysplastic syndromes (n = 16), or acute myeloid leukemia (n = 25) and B-Non-Hodgkin lymphoma (n = 9) with BM infiltration and acute lymphoblastic leukemia (n = 9) were analyzed for their functionality and by RNA sequencing. A reduced growth and differentiation capacity of MSCs was found in all entities. RNA sequencing distinguished both groups but clearly showed overlapping differentially expressed genes, including major players in the BMP/TGF and WNT-signaling pathway which are crucial for growth, osteogenesis, and hematopoiesis. Functional alterations in healthy MSCs were inducible by exposure to supernatants from malignant cells, implicating the involvement of these factors in disease progression. Overall, we were able to identify overlapping factors that pose potential future therapeutic targets. Full article

A 13-year-old male undergoing maintenance chemotherapy with methotrexate and 6-mercaptopurine (6MP), for very high-risk B-cell acute lymphoblastic leukemia (ALL), presented with vomiting due to severe hypoglycemia with metabolic acidosis. While his laboratory values were concerning for a critically ill child, the patient was relatively well appearing. Hypoglycemia is a rare but serious side effect of 6MP with an unexpectedly variable presentation; therefore, a high index of suspicion is needed for its prompt detection and treatment. This patient also had severe metabolic acidosis, likely secondary to hypoglycemia, creating a serious clinical picture despite a well-appearing child. This example of incongruity between laboratory tests and clinical appearance adds nuance to the existing literature. Moreover, although 6MP-associated hypoglycemia is rare, it may be more prevalent than the literature suggests, as symptoms of hypoglycemia—nausea, vomiting, and somnolence—mirror common chemotherapy side effects. 6MP-induced hypoglycemia can be ameliorated with the addition of allopurinol to shunt metabolism in favor of the production of therapeutic metabolites over hepatotoxic metabolites. Additionally, a morning administration of 6MP and frequent snacks may also help to prevent hypoglycemia. Overall, this case adds to the literature of unusual reactions to 6MP including hypoglycemia in an older child without traditional risk factors. Full article

Eosinophils in peripheral blood account for 0.3–5% of leukocytes, which is equivalent to 0.05–0.5 × 10⁹/L. A count above 0.5 × 10⁹/L is considered to indicate eosinophilia, while a count equal to or above 1.5 × 10⁹/L is defined as hypereosinophilia. In bone marrow aspirate, eosinophilia is considered when eosinophils make up more than 6% of the total nuclear cells. In daily clinical practice, the most common causes of reactive eosinophilia are non-hematologic, whether they are non-neoplastic (allergic diseases, drugs, infections, or immunological diseases) or neoplastic (solid tumors). Eosinophilia that is associated with a hematological malignancy may be reactive or secondary to the production of eosinophilopoietic cytokines, and this is mainly seen in lymphoid neoplasms (Hodgkin lymphoma, mature T-cell neoplasms, lymphocytic variant of hypereosinophilic syndrome, and B-acute lymphoblastic leukemia/lymphoma). Eosinophilia that is associated with a hematological malignancy may also be neoplastic or primary, derived from the malignant clone, usually in myeloid neoplasms or with its origin in stem cells (myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, acute myeloid leukemia with core binding factor translocations, mastocytosis, myeloproliferative neoplasms, myelodysplastic/myeloproliferative neoplasms, and myelodysplastic neoplasms). There are no concrete data in standardized cytological and cytometric procedures that could predict whether eosinophilia is reactive or clonal. The verification is usually indirect, based on the categorization of the accompanying hematologic malignancy. This review focuses on the broad differential diagnosis of hematological malignancies with eosinophilia. Full article

Approximately 25% of children with B-cell precursor acute lymphoblastic leukemia (pB-ALL) harbor the t(12;21)(p13;q22) translocation, leading to the ETV6::RUNX1 (E::R) fusion gene. This translocation occurs in utero, but the disease is much less common than the prevalence of the fusion in newborns, suggesting that secondary mutations are required for overt leukemia. The role of these secondary mutations remains unclear and may contribute to treatment resistance and disease recurrence. We developed a zebrafish model for E::R leukemia using CRISPR/Cas9 to introduce the human RUNX1 gene into zebrafish etv6 intron 5, resulting in E::R fusion gene expression controlled by the endogenous etv6 promoter. As seen by GFP fluorescence at a single-cell level, the model correctly expressed the fusion protein in the right places in zebrafish embryos. The E::R fusion expression induced an expansion of the progenitor cell pool and led to a low 2% frequency of leukemia. The introduction of targeted pax5 and cdkn2a/b gene mutations, mimicking secondary mutations, in the E::R line significantly increased the incidence in leukemia. Transcriptomics revealed that the E::R;pax5mut leukemias exclusively represented B-lineage disease. This novel E::R zebrafish model faithfully recapitulates human disease and offers a valuable tool for a more detailed analysis of disease biology in this subtype. Full article

Adult acute lymphoblastic leukemia (ALL) is associated with poor outcomes. ALL is initiated by primary aberrations, but secondary genetic lesions are necessary for overt ALL. In this study, we reassessed the value of primary and secondary aberrations in intensively treated ALL patients in relation to mutator enzyme expression. RT-PCR, genomic PCR, and sequencing were applied to evaluate primary aberrations, while qPCR was used to measure the expression of RAG and AID mutator enzymes in 166 adult ALL patients. Secondary copy number alterations (CNA) were studied in 94 cases by MLPA assay. Primary aberrations alone stratified 30% of the patients (27% high-risk, 3% low-risk cases). The remaining 70% intermediate-risk patients included BCR::ABL1^pos subgroup and ALL lacking identified genetic markers (NEG ALL). We identified three CNA profiles: high-risk bad-CNA (CNA^high/IKZF1^pos), low-risk good-CNA (all other CNAs), and intermediate-risk CNA^neg. Furthermore, based on RAG/AID expression, we report possible mechanisms underlying the CNA profiles associated with poor outcome: AID stratified outcome in CNA^neg, which accompanied most likely a particular profile of single nucleotide variations, while RAG in CNA^pos increased the odds for CNA^high/IKZF1^pos development. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% of BCR::ABL1^pos and NEG patients. Full article

The multi-kinase inhibitor dasatinib has been implicated to be effective in pre-B-cell receptor (pre-BCR)-positive acute lymphoblastic leukemia (ALL) expressing the E2A-PBX1 fusion oncoprotein. The TGFβ signaling pathway is involved in a wide variety of cellular processes, including embryonic development and cell homeostasis, and it can have dual roles in cancer: suppressing tumor growth at early stages and mediating tumor progression at later stages. In this study, we identified the upregulation of the TGFβ signaling pathway in our previously generated human dasatinib-resistant pre-BCR⁺/E2A-PBX1⁺ ALL cells using global transcriptomic analysis. We confirm the upregulation of the TGFβ pathway member SMAD3 at the transcriptional and translational levels in dasatinib-resistant pre-BCR⁺/E2A-PBX1⁺ ALL cells. Hence, dasatinib blocks, at least partially, TGFβ-induced SMAD3 phosphorylation in several B-cell precursor (BCP) ALL cell lines as well as in dasatinib-resistant pre-BCR⁺/E2A-PBX1⁺ ALL cells. Activation of the TGFβ signaling pathway by TGF-β1 leads to growth inhibition by cell cycle arrest at the G0/G1 stage, increase in apoptosis and transcriptional changes of SMAD-targeted genes, e.g. c-MYC downregulation, in pre-BCR+/E2A-PBX1+ ALL cells. These results provide a better understanding about the role that the TGFβ signaling pathway plays in leukemogenesis of BCP-ALL as well as in secondary drug resistance to dasatinib. Full article

ETV6-ABL1 gene fusion is a rare genetic rearrangement in a variety of malignancies, including myeloproliferative neoplasms (MPN), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). Here, we report the case of a 16-year-old male diagnosed with a MPN, 7 months post-completion of treatment for Burkitt leukaemia. RNA sequencing analysis confirmed the presence of an ETV6-ABL1 fusion transcript, with an intact, in-frame ABL tyrosine–kinase domain. Of note, secondary ETV6-ABL1-rearranged neoplastic diseases have not been reported to date. The patient was started on a tyrosine kinase inhibitor (TKI; imatinib) and, subsequently, underwent a 10/10 matched unrelated haematopoietic stem cell transplant. He is disease-free five years post-transplant. Definitive evidence of the prognostic influence of the ETV6-ABL1 fusion in haematological neoplasms is lacking; however, overall data suggest that it is a poor prognostic factor, particularly in patients with ALL and AML. The presence of this ETV6-ABL1 fusion should be more routinely investigated, especially in patients with a CML-like picture. More routine use of whole-genome and RNA sequencing analyses in clinical diagnostic care, in conjunction with conventional cytogenetics, will facilitate these investigations. Full article

Background: Secondary primary malignancies (SPM) have attracted increasing attention with the application of autologous hematopoietic stem cell transplantation (ASCT) and novel agents in multiple myeloma (MM). Secondary acute lymphoblastic leukemia (sALL) has rarely been reported, and the clinical characteristics and prognosis of sALL have not been described in detail. Methods: We retrospectively enrolled 179 consecutive newly diagnosed multiple myeloma (NDMM) patients undergoing bortezomib-based induction regimens followed by upfront ASCT and maintenance therapy from December 2006 to April 2018 in our center. Results: The median follow-up interval was 69.1 months, and 12 patients (6.7%) developed sALL during maintenance therapy. The median time from the diagnosis of MM to the occurrence of sALL was 51.1 (31.7–91.5) months. All sALL patients received thalidomide as maintenance therapy before the onset of sALL, and the median duration of thalidomide maintenance was 39.5 (24–74) months. The cumulative incidence of sALL was 6.6% and 11.2% at 5 and 10 years after the diagnosis of MM, respectively. All sALL patients presented with a B-cell immunophenotype accompanied by myeloid antigen expression according to flow cytometry analysis, and the BCR/ABL fusion gene was all negative. Only one patient had evidence of active MM, and the other patients were in stable status at the time of the diagnosis of sALL. The prognosis of most sALL patients was very poor, and the median overall survival time was 11.9 (1.1–51.2) months since the diagnosis of sALL. Conclusions: sALL should be considered for MM patients who developed unexplained persistent cytopenia while on long-term thalidomide maintenance treatment, particularly if it has been more than 3 years. With the increasing availability of new drugs for MM, thalidomide may be recommended for no more than 3 years. Sequential allogeneic hematopoietic stem cell transplantation was considered as soon as possible after achieving remission in order to achieve a longer survival. Full article

The most frequent chromosomal rearrangement in childhood B-cell acute lymphoblastic leukemia (B-ALL) is translocation t(12;21)(p13;q22). It results in the fusion of the ETV6::RUNX1 gene, which is active in the regulation of multiple crucial cellular pathways. Recent studies hypothesize that many translocations are influenced by RAG-initiated deletions, as well as defects in the RAS and NRAS pathways. According to a “two-hit” model for the molecular pathogenesis of pediatric ETV6::RUNX1-positive B-ALL, the t(12;21) translocation requires leukemia-causing secondary mutations. Patients with ETV6::RUNX1 express up to 60 different aberrations, which highlights the heterogeneity of this B-ALL subtype and is reflected in differences in patient response to treatment and chances of relapse. Most studies of secondary genetic changes have concentrated on deletions of the normal, non-rearranged ETV6 allele. Other predominant structural changes included deletions of chromosomes 6q and 9p, loss of entire chromosomes X, 8, and 13, duplications of chromosome 4q, or trisomy of chromosomes 21 and 16, but the impact of these changes on overall survival remains unclarified. An equally genetically diverse group is the recently identified new B-ALL subtype ETV6::RUNX1-like ALL. In our review, we provide a comprehensive description of recurrent secondary mutations in pediatric B-ALL with t(12;21) to emphasize the value of investigating detailed molecular mechanisms in ETV6::RUNX1-positive B-ALL, both for our understanding of the etiology of the disease and for future clinical advances in patient treatment and management. Full article

Ewing sarcoma (EwS) is the second most common bone and soft tissue tumor, affecting primarily adolescents and young adults. Patients with secondary EwS are excluded from risk stratification in several studies and therefore do not benefit from new therapies. More knowledge about patients with EwS as secondary malignant neoplasms (SMN) is needed to identify at-risk patients and adapt follow-up strategies. Epidemiology, clinical characteristics, and survival analyses of EwS as SMN were analyzed in 3844 patients treated in the last three consecutive international EwS trials, EICESS 92, Euro-E.W.I.N.G. 99, and EWING 2008. Forty-two cases of EwS as SMN (approximately 1.1% of all patients) were reported, preceded by a heterogeneous group of malignancies, mainly acute lymphoblastic leukemias (n = 7) and lymphomas (n = 7). Three cases of EwS as SMN occurred in the presumed radiation field of the primary tumor. The median age at diagnosis of EwS as SMN was 19.4 years (range, 5.9–72) compared with 10.8 years (range, 0.9–51.2) for primary EwS. The median interval between first malignancy and EwS diagnosis was 7.4 years. The 3-year overall survival (OS)/event-free survival (EFS) was 0.69 (SE = 0.09)/0.53 (SE = 0.10) for localized patients and 0.36 (SE = 0.13)/0.29 (SE = 0.12) for metastatic patients (OS: p = 0.02; EFS: p = 0.03). Survival in patients with EwS as SMN did not differ between hematologic or solid primary malignancies. EwS as SMN is rare; however, survival is similar to that of primary EwS, and its risk-adjusted treatment should be curative, especially in localized patients. Full article

In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In addition, immune-dysregulation, secondary to marrow failure, has been reported as being, in some cases, the most evident and early sign of the disease and making the diagnosis of both groups of disorders challenging. Dyskeratosis congenita is a disorder characterized by premature telomere erosion, typically showing marrow failure, nail dystrophy and leukoplakia, although incomplete genetic penetrance and phenotypes with immune-dysregulation features have been described. We report on a previously healthy 17-year-old girl, with a cousin successfully treated for acute lymphoblastic leukemia, who presented with leukopenia and neutropenia. The diagnostic work-up showed positive anti-neutrophil antibodies, leading to the diagnosis of autoimmune neutropenia, a slightly low NK count and high TCR-αβ+-double-negative T-cells. A next-generation sequencing (NGS) analysis showed the 734C>A variant on exon 6 of the TINF2 gene, leading to the p.Ser245Tyr. The telomere length was short on the lymphocytes and granulocytes, suggesting the diagnosis of an atypical telomeropathy showing with immune-dysregulation. This case underlines the importance of an accurate diagnostic work-up of patients with immune-dysregulation, who should undergo NGS or whole exome sequencing to identify specific disorders that deserve targeted follow-up and treatment. Full article