Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia

Perez, B.; Méchinaud, Françoise; Garrigue, Claire; Romdhane, Neïla Ben; Isidor, B.; Philip, Nicole; Derain-Court, J; Cassinat, Bruno; Lachenaud, Julie; Kaltenbach, Sophie; Salmon, Asher; Désirée, C; Pereira, Sabrina Bernárdez; Menot, M L; Royer, Nicolas; Fenneteau, Odile; Baruchel, André; Chomienne, Christine; Verloes, Alain; Cavé, Hélène

doi:10.1136/jmg.2010.076836

Cited by 135 publications

(114 citation statements)

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“…A number of children with JMML harboring these homozygous CBL mutations shared phenotypic features, suggesting that these lesions might first occur as germline events (82)(83)(84). Additional studies indicate that these mutations are autosomally inherited in a dominant fashion approximately 50% of the time (82).…”

Section: Patients With Genetic Syndromes Provided Important Clues To mentioning

confidence: 99%

Advances in the Genetics of High-Risk Childhood B-Progenitor Acute Lymphoblastic Leukemia and Juvenile Myelomonocytic Leukemia: Implications for Therapy

Loh

Mullighan

2012

Clinical Cancer Research

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Hematologic malignancies of childhood comprise the most common childhood cancers. These neoplasms derive from the pathologic clonal expansion of an abnormal cancer-initiating cell and span a diverse spectrum of phenotypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). Expansion of immature lymphoid or myeloid blasts with suppression of normal hematopoiesis is the hallmark of ALL and AML, whereas MPN is associated with proliferation of 1 or more lineages that retain the ability to differentiate, and MDS is characterized by abnormal hematopoiesis and cytopenias. The outcomes for children with the most common childhood cancer, B-progenitor ALL (B-ALL), in general, is quite favorable, in contrast to children affected by myeloid malignancies. The advent of highly sensitive genomic technologies reveals the remarkable genetic complexity of multiple subsets of high-risk B-progenitor ALL, in contrast to a somewhat simpler model of myeloid neoplasms, although a number of recently discovered alterations displayed by both types of malignancies may lead to common therapeutic approaches. This review outlines recent advances in our understanding of the genetic underpinnings of high-risk B-ALL and juvenile myelomonocytic leukemia, an overlap MPN/MDS found exclusively in children, and we also discuss novel therapeutic approaches that are currently being tested in clinical trials. Recent insights into the clonal heterogeneity of leukemic samples and the implications for diagnostic and therapeutic approaches are also discussed. Clin Cancer Res; 18(10); 2754-67. Ó2012 AACR. Acute Lymphoblastic LeukemiaAcute lymphoblastic leukemia (ALL) is the commonest childhood malignancy and, despite progressive improvements in the outcome of therapy, remains the leading cause of cancer-related death in children and young adults (1). ALL is characterized by accumulation of immature lymphoid progenitors in the bone marrow, peripheral blood, and central nervous system and results in death from the consequences of bone marrow failure: anemia, neutropenia and infection, and thrombocytopenia and bleeding. Although these features are common to all patients, ALL represents a remarkably diverse range of subtypes characterized by distinct constellations of gross and submicroscopic genetic alterations, including chromosomal translocations, structural variants, and DNA sequence mutations.Many of these lesions are central events in leukemogenesis, and several are also important determinants of the risk of treatment failure and relapse. General overviews of the genetic basis of ALL may be found in several recent excellent reviews (2-6). This review is part of a series of articles in this issue reviewing new genetic insights and therapeutic opportunities in childhood malignancies (7-11). Here, we briefly review key chromosomal rearrangements in ALL and then focus on several high-risk subtypes, which have hitherto been poorly understood and for which r...

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Section: Patients With Genetic Syndromes Provided Important Clues To mentioning

confidence: 99%

Advances in the Genetics of High-Risk Childhood B-Progenitor Acute Lymphoblastic Leukemia and Juvenile Myelomonocytic Leukemia: Implications for Therapy

Loh

Mullighan

2012

Clinical Cancer Research

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“…[74][75][76][77] Unexpectedly, a high percentage of children with JMML and CBL mutations had been noted to have developmental delay, cryptorchidism and impaired growth. 15 In fact, and in contrast to adult MPN, children with JMML and CBL mutations were found to have a germline CBL missense mutation.…”

Section: Juvenile Myelomonocytic Leukemia With Noonan-like Cbl Syndromementioning

confidence: 99%

“…Like in NF-1, leukemic cells displayed the germline mutation on one allele and acquired LOH on the other allele. 15,16,76 Children with this germline CBL disorder display a NS-like phenotpye (Table 1). 15,78 CBL, originally discovered as the cellular homolog of the v-Cbl oncogene (reviewed by Kales et al 79 ), is a member of a family of RING finger ubiquitin ligases that is responsible for the intracellular transport and degradation of a large number of receptor tyrosine kinases but also retains important adaptor functions.…”

Section: Juvenile Myelomonocytic Leukemia With Noonan-like Cbl Syndromementioning

confidence: 99%

RAS diseases in children

Niemeyer

2014

Haematologica

127

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REVIEW ARTICLES 1653 IntroductionDiscoveries made about 50 years ago revealed the transforming power of the Harvey and Kirsten murine sarcoma retroviruses by a set of genes named RAS genes for their role in forming rat sarcomas. Subsequently, the contribution of RAS genes to cancer pathogenesis has been studied extensively. While the somatic dysregulation of RAS is a primary driver of cancer, there is a class of developmental disorders caused by germline mutations (as opposed to the somatic mutations found in cancer) in genes that encode components of the RAS signaling pathway. This chapter summarizes hematologic disturbances and cancer predisposition of these genetic disorders named "RASopathies". It will focus on juvenile myelomonocytic leukemia (JMML), an infant leukemia with initiating germline and somatic mutations in genes of the RAS signal transduction pathway. RAS and the RAS/mitogen-activated protein kinase signaling cascadeRAS turned out to be an essential cellular hub for a wide variety of signaling pathways including the three human RAS genes, KRAS, NRAS and HRAS (reviewed by Stephen et al. 1). RAS proteins act as molecular switches by cycling between an active guanosine triphospate (GTP)-bound (RAS-GTP) and an inactive guanosine diphosphate (GDP)-bound (RAS-GDP) conformation (Figure 1).2 RAS-GTP concentrations are tightly regulated by the competitive action of guanosin exchange factors (GEFs) and GTPase activating proteins (GAPs).RAS is activated by extracellular stimuli such as growth factor binding to receptor tyrosine kinases (RTKs) followed by RTK autophosphorylation and the creation of docking sites for adaptor molecules (e.g. GRB2). These molecules recruit and activate GEFs (e.g. SOS1) which displace GDP from RAS allowing RAS to bind to GTP. RAS-GTP binds to and activates a large number of effector pathways. The RAS-mediated mitogen-activated kinase (MAPK) pathway is one of several important downstream cascades. Activated RAS binds to RAF (RAF1, also known as CRAF, BRAF), the first MAPK of the signaling cascade. RAF phosphorylates MEK1 and/or MEK2, which in turn activate ERK1 and/or ERK2. Active ERKs serve as regulators of a large number of downstream processes both in the cytosol and nucleus.

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“…20 An inherited mutation of the TET2 gene causing a frame shift and premature stop was recently identified in a patient with PV. 21 Furthermore, germline CBL mutations were reported in patients with juvenile myelomonocytic leukemia, 22 but their role in familial MPN remains to be elucidated. The aim of this study was to investigate the pathogenic relevance of mutations of JAK2, TET2, CBL and MPL genes in familial clustering of MPN.…”

Section: Introductionmentioning

confidence: 99%

“…21 There is a recent report of inherited mutations of the CBL gene in juvenile myelomonocytic leukemia. 22 In order to gain further insights into the role of TET2, CBL and MPL mutations in familial clustering of MPN, we analyzed the sequence of these genes in a unique cohort of 88 patients with familial MPN. In summary, we could not identify mutations of TET2, CBL or MPL that are inherited and segregate with the disease in our cohort of patients with familial MPN.…”

mentioning

confidence: 99%

The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative neoplasms

Olcaydu¹,

Rumi²,

Harutyunyan³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMyeloproliferative neoplasms constitute a group of diverse chronic myeloid malignancies that share pathogenic features such as acquired mutations in the JAK2, TET2, CBL and MPL genes. There are recent reports that a JAK2 gene haplotype (GGCC or 46/1) confers susceptibility to JAK2 mutation-positive myeloproliferative neoplasms. The aim of this study was to examine the role of the JAK2 GGCC haplotype and germline mutations of TET2, CBL and MPL in familial myeloproliferative neoplasms. Design and MethodsWe investigated patients with familial (n=88) or sporadic (n=684) myeloproliferative neoplasms, and a control population (n=203) from the same demographic area in Italy. Association analysis was performed using tagged single nucleotide polymorphisms (rs10974944 and rs12343867) of the JAK2 haplotype. Sequence analysis of TET2, CBL and MPL was conducted in the 88 patients with familial myeloproliferative neoplasms. ResultsAssociation analysis revealed no difference in haplotype frequency between familial and sporadic cases of myeloproliferative neoplasms (P=0.6529). No germline mutations in TET2, CBL or MPL that segregate with the disease phenotype were identified. As we observed variability in somatic mutations in the affected members of a pedigree with myeloproliferative neoplasms, we postulated that somatic mutagenesis is increased in familial myeloproliferative neoplasms. Accordingly, we compared the incidence of malignant disorders between sporadic and familial patients. Although the overall incidence of malignant disorders did not differ significantly between cases of familial and sporadic myeloproliferative neoplasms, malignancies were more frequent in patients with familial disease aged between 50 to 70 years (P=0.0198) than in patients in the same age range with sporadic myeloproliferative neoplasms. ConclusionsWe conclude that the JAK2 GGCC haplotype and germline mutations of TET2, CBL or MPL do not explain familial clustering of myeloproliferative neoplasms. As we observed an increased frequency of malignant disorders in patients with familial myeloproliferative neoplasms, we hypothesize that the germline genetic lesions that underlie familial clustering of myeloproliferative neoplasms predispose to somatic mutagenesis that is not restricted to myeloid hematopoietic cells but cause an increase in overall carcinogenesis. Haematologica 2011;96(3):367-374. doi:10.3324/haematol.2010 This is an open-access paper.

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Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia

Abstract: A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

Cited by 135 publications

References 29 publications

Advances in the Genetics of High-Risk Childhood B-Progenitor Acute Lymphoblastic Leukemia and Juvenile Myelomonocytic Leukemia: Implications for Therapy

Advances in the Genetics of High-Risk Childhood B-Progenitor Acute Lymphoblastic Leukemia and Juvenile Myelomonocytic Leukemia: Implications for Therapy

RAS diseases in children

The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative neoplasms

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