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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Juvenile myelomonocytic leukemia (JMML) is an uncommon, aggressive childhood malignancy. Its initiating pathogenetic event appears to be hyperactivation of the RAS pathway, as a result of mutations in a limited set of genes, PTPN11, NF1, NRAS, KRAS, or CBL, in over 90% of patients. Mutations in SETBP1 or JAK3 and monosomy 7 (-7) have been observed in about 25% of patients.144 A novel fetal-like molecular subgroup with LIN28B overexpression with high age-adjusted fetal hemoglobin (HbF) levels has been described. Uniquely, most patients with JMML exhibit an increased in vitro sensitivity to GM-CSF, which appears to augment signaling of other downstream effectors, in particular JAK/STAT5. Although JMML shares some clinical features with CMML, such as monocytosis and hepatosplenomegaly, the molecular features are quite distinct by the absence of mutations in epigenetic and splicing modifiers. Congenital JMML predisposition syndromes exist, particularly neurofibromatosis and Noonan syndrome, which converge on RAS/MAPK signaling abnormalities and markedly increase the risk of developing JMML. The natural history of JMML is variable, with some patients, particularly those with Noonan syndrome or CBL syndrome, having spontaneous resolution of their disease despite identification of clonal hematopoiesis, while others can have a fulminant clinical course, and DNA-methylating patterns might improve prediction of outcomes.
Schinzel−Giedion Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
In contrast to germline variants that are responsible for the onset of SGS and increased risk for embryonal tumors, somatic SETBP1 mutations tend to occur in patients with hematologic neoplasms, including acute myeloid leukemia (AML, <1% of cases), myeloproliferative neoplasm (MPN, 4%), myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes (MDS/MPN, 9%), myelodysplastic syndrome (MDS, 2–3%), juvenile myelomonocytic leukemia (JMML, 8–10%), chronic myelomonocytic leukemia (CMML, 15–19%), chronic neutrophilic leukemia (CNL, 10–38%), and atypical chronic myeloid leukemia (aCML, 30%) [4–16]. Most cases are associated with heterozygous missense mutations, and only a few cases show a homozygous mutation. SETBP1 involvement in leukemia transformation is mainly through activation of the HOXA9 and HOXA10 genes, and subsequent increase in leukemic cell proliferation [17]. Somatic SETBP1 mutations observed in hematologic neoplasms appear to have a gain-of-function effect on the SETBP1 protein, leading to decreased binding of the βTrCP1 and increased protein levels. The somatic variants in hematologic neoplasms appear more disruptive than the germline variants in SGS, and patients with myeloid malignancies harboring SETBP1-mutations often have a significantly inferior overall survival and increased risk of disease progression [18–20].
Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Juvenile myelomonocytic leukaemia (JMML) is arguably considered, after CML, one of the best biologically understood haematological malignancy. It is a rare, aggressive childhood malignancy and its initiating pathogenetic event appears to be hyperactivation of the RAS pathway, as a result of mutations in a limited set of genes, PTPN11, NF1, NRAS, KRAS or CBL in over 90% of patients. Rarely, mutations in SETBP1 or JAK3 can also be identified and monosomy 7 (-7) is noted in about 25% of patients (Table 8.8). The notable absence of global mutations in particular, affecting epigenetic and splicing genes often seen in myeloid malignancies, is noteworthy. A novel fetal-like molecular subgroup with LIN28B overexpression with high age-adjusted fetal haemoglobin (HbF) levels was described. Uniquely, most patients with JMML exhibit an increased in vitro sensitivity to GM-CSF, which appears to augment signalling of other downstream effectors, in particular JAK/STAT5.
Acute myeloid leukemia in a child with familial platelet disorder and a cryptic runx1 intragenic deletion
Published in Pediatric Hematology and Oncology, 2022
Lois M. Dodson, Kristen J. Kurtz, Andrea N. Marcogliese, Brian D. Friend, Alexandra M. Stevens, Kevin E. Fisher
Thrombocytopenia, a strong family history of hematologic malignancies, and a germline RUNX1 pathogenic variant are diagnostic of FPD-MM. As illustrated by the pedigree (Figure 1A), FPD-MM can predispose not only to AML but to various hematologic malignancies.1,4 Given our patient’s protracted presentation, monocytosis, elevated HbF, and somatic NF1 mutation, we suspect that she may have initially met diagnostic criteria for juvenile myelomonocytic leukemia (JMML) that then progressed to AML. A case of JMML has been previously reported in a child with FPD-MM with a somatic mutation in SH2B3.5 Our patient’s leukemia demonstrated a poor response to induction therapy though we were ultimately able to achieve MRD negativity and proceed with HSCT. She also exhibited significant therapy-related complications, most notably severe CPX-related rash and fevers. For children with FPD-MM AML, optimal treatment and long-term outcome data are limited and should be the focus of future investigations.
Wilms’ tumor 1 mRNA expression: a good tool for differentiating between myelodysplastic syndrome and aplastic anemia in children?
Published in Hematology, 2019
Yingxi Zuo, Yifei Cheng, Leping Zhang, Yazhen Qin, Hong Luo
This retrospective study evaluated 94 children with MDS (83 patients with refractory cytopenia of childhood [RCC], 6 patients with refractory anemia with excess blasts [RAEB], and 5 patients with juvenile myelomonocytic leukemia [JMML]) who were treated at the Department of Paediatrics in People’s Hospital Peking University between February 2008 and July 2014. These patients all fulfilled the ‘minimal diagnostic criteria’ for MDS [18], which were based on the French-American-British morphological criteria, bone marrow biopsy, immunophenotyping and chromosome karyotyping. We excluded children with therapy-related MDS. Eighty-two patients with MDS-RCC received cyclosporine and androgen as their first-line therapy. All patients and/or their guardians had provided informed consent for treatment.
Novel approaches to diagnosis and treatment of Juvenile Myelomonocytic Leukemia
Published in Expert Review of Hematology, 2018
Franco Locatelli, Mattia Algeri, Pietro Merli, Luisa Strocchio
Juvenile myelomonocytic leukemia (JMML) is an aggressive, clonal hematopoietic disorder of infancy and early childhood, resulting from oncogenic mutations in genes involved in the Ras signaling pathway.Most patients experience an aggressive clinical course, but for some children long-term survival with no or minimal treatment has been reported.Recent progress in defining the genomic landscape of JMML made a substantial contribution to the understanding of disease pathogenesis, with molecular testing taking a fundamental role in the diagnostic process.Allogeneic hematopoietic stem cell transplantation is the only established potentially curative treatment, being able to cure more than 50% of patients.Enhanced understanding of driver mutations and mechanisms underlying JMML have led to research efforts on developing novel therapeutic approaches targeting relevant nodes of JMML leukemogenesis.Among the novel therapies explored in the last years, use of 5-azacytidine appears promising for reducing disease burden and obtaining disease control both in the pre-HSCT window and in non-transplant settings.