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Anita F Oliveira, Aline Tansini, Daniel O Vidal, Luiz F Lopes, Konradin Metze, Irene Lorand-Metze
BACKGROUND: Immunophenotyping of bone marrow (BM) hemopoietic precursors is useful for diagnosis of adult myelodysplastic syndrome (MDS), but data concerning pediatric patients are limited. We analyzed immunophenotypic features of BM cells at diagnosis of children who were referred to the Brazilian Pediatric Cooperative Group of Myelodysplastic Syndromes. METHODS: Diagnosis was based on clinical information, peripheral blood counts, BM cytology and cytogenetics...
October 17, 2016: Pediatric Blood & Cancer
Chetasi Talati, Eric Padron
According to the recently published 2016 World Health Organization (WHO) classification of myeloid malignancies, myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include atypical chronic myeloid leukemia (aCML), MDS/MPN-unclassifiable (MDS/MPN-U), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and MDS/MPN ring sideroblasts with thrombocytosis (MDS/MPN-RS-T). MDS/MPN-RS-T was previously a provisional category known as refractory anemia with ring sideroblasts with thrombocytosis (RARS-T) which has now attained a distinct designation in the 2016 WHO classification...
September 24, 2016: Current Hematologic Malignancy Reports
Wei An, Bhopal C Mohapatra, Neha Zutshi, Timothy A Bielecki, Benjamin T Goez, Haitao Luan, Fany Iseka, Insha Mushtaq, Matthew D Storck, Vimla Band, Hamid Band
CBL and CBL-B ubiquitin ligases play key roles in hematopoietic stem cell homeostasis and their aberrations are linked to leukemogenesis. Mutations of CBL, often genetically-inherited, are particularly common in Juvenile Myelomonocytic Leukemia (JMML), a disease that manifests early in children. JMML is fatal unless corrected by bone marrow transplant, which is effective in only half of the recipients, stressing the need for animal models that recapitulate the key clinical features of this disease. However, mouse models established so far only develop hematological malignancy in adult animals...
July 16, 2016: Oncotarget
Pier Paolo Leoncini, Alice Bertaina, Dimitrios Papaioannou, Christian Flotho, Riccardo Masetti, Silvia Bresolin, Giuseppe Menna, Nicola Santoro, Marco Zecca, Giuseppe Basso, Giovanni Nigita, Dario Veneziano, Sara Pagotto, Katia D'Ovidio, Rossella Rota, Adrienne Dorrance, Carlo M Croce, Charlotte Niemeyer, Franco Locatelli, Ramiro Garzon
Juvenile myelomonocytic leukemia (JMML) is an aggressive leukemia of early childhood characterized by aberrant proliferation of myelomonocytic cells and hypersensitivity to GM-CSF stimulation. Mutually exclusive mutations in the RAS/ERK pathway genes such as PTPN11, NRAS, KRAS, CBL, or NF1 are found in ~90% of the cases. These mutations give rise to disease at least in part by activating STAT5 through phosphorylation and by promoting cell growth. MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression, which are often deregulated in leukemia...
July 13, 2016: Oncotarget
Rajesh B Patil, Chandrakala Shanmukhaiah, Farah Jijina, Shailesh Bamborde, Nilesh Wasekar, Manoj Toshniwal, Aniket Mohite, Vinod Patil
Objective. The aim of this paper is to report the case of Wiskott-Aldrich syndrome (WAS) that presented with unusual laboratory features. Clinical Presentation and Intervention. Male neonate admitted with symptoms related to thrombocytopenia, whose initial diagnosis was considered as neonatal alloimmune thrombocytopenia and JMML (juvenile myelomonocytic leukemia) but subsequently diagnosis was confirmed as WAS. Conclusion. This case shows that a suspicion of WAS is warranted in the setting of neonatal thrombocytopenia with JMML-like blood picture and normal sized platelets...
2016: Case Reports in Hematology
Kazuo Sakashita, Kazuyuki Matsuda, Kenichi Koike
Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder that occurs during infancy and early childhood; this disorder is characterized by hypersensitivity of the myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor in vitro. JMML usually involves somatic and/or germline mutations in the genes of the RAS pathway, including PTPN11, NRAS, KRAS, NF1, and CBL, in the leukemic cells. Almost all patients with JMML experience an aggressive clinical course, and hematopoietic stem cell transplantation (HSCT) is the only curative treatment...
August 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
Isabel Hernández-Porras, Alberto J Schuhmacher, Raquel Garcia-Medina, Beatriz Jiménez, Marta Cañamero, Alba de Martino, Carmen Guerra
The Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant proportion of NS patients may also develop myeloproliferative disorders (MPDs), including juvenile myelomonocytic leukaemia (JMML). Surprisingly, scarce information is available in relation to other tumour types in these patients. We have previously developed and characterized a knock-in mouse model that carries one of the most frequent KRAS-NS-related mutations, the K-Ras(V14I) substitution, which recapitulates most of the alterations described in NS patients, including MPDs...
June 2016: Journal of Pathology
Silvia Fluhr, Melanie Boerries, Hauke Busch, Aikaterini Symeonidi, Tania Witte, Daniel B Lipka, Oliver Mücke, Peter Nöllke, Christopher Felix Krombholz, Charlotte M Niemeyer, Christoph Plass, Christian Flotho
BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm of childhood whose clinical heterogeneity is only poorly represented by gene sequence alterations. It was previously shown that aberrant DNA methylation of distinct target genes defines a more aggressive variant of JMML, but only few significant targets are known so far. To get a broader picture of disturbed CpG methylation patterns in JMML, we carried out a methylation screen of 34 candidate genes in 45 patients using quantitative mass spectrometry...
2016: Clinical Epigenetics
Sunil S Raikar, John D Scarborough, Himalee Sabnis, John Bergsagel, David Wu, Todd M Cooper, Frank G Keller, Brent L Wood, Silvia T Bunting
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-acute lymphoblastic leukemia (T-ALL) arising from a primitive precursor. We present a unique case of an infant with ETP-ALL with a missense NRAS mutation in codon 61 (c.182A>G, p.Q61R). The patient also had a minor population of non-ETP T-ALL blasts and clinical features typically associated with juvenile myelomonocytic leukemia (JMML), namely, absolute monocytosis, splenomegaly, and elevated hemoglobin F. The treatment was initiated with chemotherapy, followed by cord blood transplantation...
September 2016: Pediatric Blood & Cancer
Assem A Elghazaly, Mohmmed U Manzoor, Mai A AlMishari, Mamoun H Ibrahim
Chronic myelomonocytic leukaemia (CMML) and juvenile myelomonocytic leukaemia (JMML) are two disease entities that come under the myelodysplastic/myeloproliferative neoplasms category. Each of the two conditions has its own diagnostic criteria. In addition, they have different ages of presentation; while CMML is typically a disease of the elderly, JMML is a disease of young children. Here we are presenting the case of a 27-year-old male patient who, at the time of diagnosis, fulfilled the diagnostic criteria of both diseases...
2016: Case Reports in Oncological Medicine
Yozo Nakazawa, Kazuyuki Matsuda, Takashi Kurata, Akane Sueki, Miyuki Tanaka, Kazuo Sakashita, Chihaya Imai, Matthew H Wilson, Kenichi Koike
BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathway. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option for JMML; however, disease recurrence is a major cause of treatment failure. We investigated adoptive immunotherapy using GMR-targeted chimeric antigen receptor (CAR) for JMML...
2016: Journal of Hematology & Oncology
Silvia Bresolin, Paola De Filippi, Francesca Vendemini, Mirko D'Alia, Marco Zecca, Lueder H Meyer, Cesare Danesino, Franco Locatelli, Riccardo Masetti, Giuseppe Basso, Geertruy Te Kronnie
Juvenile myelomonocytic leukemia (JMML) is a rare aggressive disease of early childhood. Driver mutations in the Ras signaling pathways are a key feature of JMML patients. Mutations in SETBP1 and JAK3 were recently identified in a subset of JMML patients characterized by poor prognosis and progression of disease. In this study, we report the results of a screening for mutations in SETBP1 and JAK3 of a cohort of seventy Italian patients with JMML, identifying 11.4% of them harboring secondary mutations in these two genes and discovering two new mutations in the SKI domain of SETBP1...
May 17, 2016: Oncotarget
J Akutagawa, T Q Huang, I Epstein, T Chang, M Quirindongo-Crespo, C L Cottonham, M Dail, B S Slusher, L S Friedman, D Sampath, B S Braun
Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are myelodysplastic/myeloproliferative neoplasia (MDS/MPN) overlap syndromes that respond poorly to conventional treatments. Aberrant Ras activation because of NRAS, KRAS, PTPN11, CBL and NF1 mutations is common in CMML and JMML. However, no mechanism-based treatments currently exist for cancers with any of these mutations. An alternative therapeutic strategy involves targeting Ras-regulated effector pathways that are aberrantly activated in CMML and JMML, which include the Raf/MEK/ERK and phosphoinositide-3'-OH kinase (PI3K)/Akt cascades...
June 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kazuo Sakashita
Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder that occurs during infancy and early childhood; this disorder is characterized by hypersensitivity of the myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. JMML usually involves somatic and/or germline mutations in the genes of the RAS pathway, including PTPN11, NRAS, KRAS, NF1, and CBL, in the leukemic cells. Recently, additional genetic and/or epigenetic alterations have been identified in JMML, and these alterations appear to be prognostic indicators...
February 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Michiko Muraoka, Chiho Okuma, Kiichiro Kanamitsu, Hisashi Ishida, Yui Kanazawa, Kana Washio, Masafumi Seki, Motohiro Kato, Junko Takita, Yusuke Sato, Seishi Ogawa, Hirokazu Tsukahara, Megumi Oda, Akira Shimada
Juvenile myelomonocytic leukemia (JMML) appears to be a life-threatening disease and showed poor prognosis even after hematopoietic stem cell transplantation (HSCT) because of high relapse rate. On the other hand, recent molecular analysis revealed the heterogeneity of JMML. Here we report that two JMML patients survived >20 years without HSCT and both patients had uniparental disomy of 11q23 where CBL is located without the phenomenon found in neither Noonan syndrome nor Noonan syndrome-like disorder. We think that some JMML patients with CBL mutation might show the good prognosis in later life after remission of JMML...
June 2016: Journal of Human Genetics
Thomas Wilhelm, Daniel B Lipka, Tania Witte, Justyna A Wierzbinska, Silvia Fluhr, Monika Helf, Oliver Mücke, Rainer Claus, Carolin Konermann, Peter Nöllke, Charlotte M Niemeyer, Christian Flotho, Christoph Plass
A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of AKAP12 has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative high-resolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three AKAP12 promoters (i.e., α, β, and γ) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples...
2016: Epigenetics: Official Journal of the DNA Methylation Society
Y Lucy Liu, Yan Yan, Cody Webster, Lijian Shao, Shelly Y Lensing, Hongyu Ni, Wei Feng, Natalia Colorado, Rupak Pathak, Zhifu Xiang, Martin Hauer-Jensen, Shaoguang Li, Daohong Zhou, Peter D Emanuel
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN). JMML leukemogenesis is linked to a hyperactivated RAS pathway, with driver mutations in the KRAS, NRAS, NF1, PTPN11, or CBL genes. Previous murine models demonstrated how those genes contributed to the selective hypersensitivity of JMML cells to granulocyte macrophage-colony-stimulating factor (GM-CSF), a unifying characteristic in the disease. However, it is unclear what causes the early death in children with JMML, because transformation to acute leukemia is rare...
April 14, 2016: Blood
Hélène Cavé, Aurélie Caye, Nehla Ghedira, Yline Capri, Nathalie Pouvreau, Natacha Fillot, Aurélien Trimouille, Cédric Vignal, Odile Fenneteau, Yves Alembik, Jean-Luc Alessandri, Patricia Blanchet, Odile Boute, Patrice Bouvagnet, Albert David, Anne Dieux Coeslier, Bérénice Doray, Olivier Dulac, Valérie Drouin-Garraud, Marion Gérard, Delphine Héron, Bertrand Isidor, Didier Lacombe, Stanislas Lyonnet, Laurence Perrin, Marlène Rio, Joëlle Roume, Sylvie Sauvion, Annick Toutain, Catherine Vincent-Delorme, Marjorie Willems, Clarisse Baumann, Alain Verloes
Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education...
August 2016: European Journal of Human Genetics: EJHG
Hetty H Helsmoortel, Silvia Bresolin, Tim Lammens, Hélène Cavé, Peter Noellke, Aurélie Caye, Farzaneh Ghazavi, Andrica de Vries, Henrik Hasle, Veerle Labarque, Riccardo Masetti, Jan Stary, Marry M van den Heuvel-Eibrink, Jan Philippé, Nadine Van Roy, Yves Benoit, Frank Speleman, Charlotte Niemeyer, Christian Flotho, Giuseppe Basso, Geertruy Te Kronnie, Pieter Van Vlierberghe, Barbara De Moerloose
Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed...
March 3, 2016: Blood
Julien Haroche, Oussama Abla
Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim-Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously...
2015: Hematology—the Education Program of the American Society of Hematology
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