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1.
Blood ; 143(25): 2627-2643, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38513239

RESUMEN

ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.


Asunto(s)
Síndrome de Down , Mutación , Humanos , Síndrome de Down/genética , Síndrome de Down/complicaciones , Masculino , Femenino , Reacción Leucemoide/genética , Lactante , Preescolar , Secuenciación del Exoma , Pronóstico , Leucemia Mieloide/genética , Recién Nacido , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética
2.
J Pediatr Hematol Oncol ; 43(8): e1173-e1176, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-33625081

RESUMEN

Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.


Asunto(s)
Hipersensibilidad a las Drogas/patología , Homocigoto , Mercaptopurina/efectos adversos , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirofosfatasas/genética , Antimetabolitos Antineoplásicos , Infarto Encefálico/inducido químicamente , Infarto Encefálico/genética , Infarto Encefálico/patología , Preescolar , Hipersensibilidad a las Drogas/etiología , Humanos , Infecciones/inducido químicamente , Infecciones/genética , Infecciones/patología , Linfohistiocitosis Hemofagocítica/inducido químicamente , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/patología , Masculino , Mucositis/inducido químicamente , Mucositis/genética , Mucositis/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Sepsis/inducido químicamente , Sepsis/genética , Sepsis/patología
3.
Pediatr Blood Cancer ; 67(4): e28188, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32020774

RESUMEN

BACKGROUND: Transient abnormal myelopoiesis (TAM) is a unique myeloproliferative disorder that occurs in neonates with constitutional trisomy 21/Down syndrome (DS). Although TAM also develops in neonates without constitutional trisomy 21, the clinical, cytogenetic, and molecular characteristics of those patients are not fully understood. PROCEDURE: We retrospectively evaluated the clinical and cytogenetic findings and GATA1 mutation status of 17 neonates with TAM and nonconstitutional trisomy 21 tested for GATA1 mutations at our institute, and compared the findings with those of 64 neonates with TAM and constitutional trisomy 21/DS. RESULTS: DS clinical features were observed in five of the 17 (29%) patients. In all patients, both trisomy 21 and GATA1 mutations were detected in diagnostic samples. Over a median follow-up of 33 (range, 0-139) months, early death (< 6 months of age) occurred in four patients (24%). Overall and event-free survivals were not significantly different between the patients with TAM and nonconstitutional trisomy 21 and those with TAM and constitutional trisomy 21/DS (five-year overall survival: 76% ± 10% vs 53% ± 13%, P = 0.40; five-year event-free survival: 55% ± 13% vs 48% ± 12%, P = 0.90). The five-year cumulative incidence of progression to myeloid leukemia of DS was also similar between the groups (21% vs 24%, P = 0.80). CONCLUSIONS: Patients with TAM and nonconstitutional trisomy 21 exhibited similar biology and outcomes to those with TAM and constitutional trisomy 21/DS. The possibility of TAM should be considered even in phenotypically normal neonates with TAM symptoms, for appropriate management.


Asunto(s)
Cromosomas Humanos Par 21/genética , Síndrome de Down , Factor de Transcripción GATA1/genética , Mutación , Mielopoyesis/genética , Supervivencia sin Enfermedad , Síndrome de Down/genética , Síndrome de Down/mortalidad , Síndrome de Down/patología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Tasa de Supervivencia
4.
Exp Hematol ; 132: 104179, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38342295

RESUMEN

Myeloid leukemia associated with Down syndrome (ML-DS) responds well to chemotherapy and has a favorable prognosis, but the clinical outcome of patients with refractory or relapsed ML-DS is dismal. We recently reported a case of relapsed ML-DS with an effective response to a DNA methyltransferase inhibitor, azacitidine (AZA). However, the efficacy of AZA for refractory or relapsed ML-DS remains uncertain. Here, we investigated the effects and mechanism of action of AZA on three ML-DS cell lines derived from relapsed cases. AZA inhibited the proliferation of all examined ML-DS cell lines to the same extent as that of AZA-sensitive acute myeloid leukemia non-Down syndrome cell lines. Transient low-dose AZA treatment exerted durable antileukemic effects on ML-DS cells. The inhibitory effect included cell cycle arrest, apoptosis, and reduction of aldehyde dehydrogenase activity. Comprehensive differential gene expression analysis showed that AZA induced megakaryocytic differentiation in all ML-DS cell lines examined. Furthermore, AZA induced activation of type I interferon-stimulated genes, primarily involved in antiproliferation signaling, without stimulation of the interferon receptor-mediated autocrine system. Activation of the type I interferon pathway by stimulation with interferon-α exerted antiproliferative effects on ML-DS cells, suggesting that AZA exerts its antileukemic effects on ML-DS cells at least partially through the type I interferon pathway. Moreover, the effect of AZA on normal hematopoiesis did not differ significantly between individuals with non-Down syndrome and Down syndrome. In summary, this study suggests that AZA is a potentially effective treatment option for ML-DS disease control, including relapsed cases, and has reduced side effects.


Asunto(s)
Azacitidina , Síndrome de Down , Inhibidores Enzimáticos , Interferón Tipo I , Leucemia Mieloide Aguda , Humanos , Azacitidina/farmacología , Azacitidina/uso terapéutico , Línea Celular , ADN , Síndrome de Down/complicaciones , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/genética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Metiltransferasas
5.
J Gen Fam Med ; 24(4): 223-230, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37484134

RESUMEN

Background: Compression therapy using compression material is often used for umbilical hernias in infants; however, there are problems regarding its use, such as appearance and cost. In our hospital, we use the tape fixation method without compression materials. We report the effectiveness of this method, its significance in measuring the degree of hernia bulge before treatment, and parent satisfaction with the treatment. Methods: We analyzed 77 cases of umbilical hernias (41 boys and 36 girls, mean age 52.7 ± 18.3 days) that were treated with the tape fixation method at the Department of Pediatrics of our hospital. Hernia size was classified based on the height of the bulge: mild (<1 cm), moderate (1≦ and <3 cm), or severe (>3 cm). Treatment duration was compared between the groups using the Steel-Dwass test. After the treatment, a questionnaire was mailed to the parents to assess the treatment satisfaction. Results: Seventy-three patients (94.8%) achieved closure of the hernia orifice, with no excess skin and a well-shaped umbilicus. The duration of treatment was significantly shorter, with the following order: mild (18.5 ± 8.2 days), moderate (25.0 ± 11.9 days), and severe cases (47.8 ± 11.7 days). According to the questionnaire, 97.5% of the parents were satisfied with the treatment. Conclusions: Our tape fixation method without compression material achieved a high closure rate and a good shape of the umbilicus. In addition, we noted that the height of the hernia bulge can be used as a guide to estimate the duration of treatment.

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