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We reviewed the clinical features, treatment, and outcome of 100 children with myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), and acute myeloid leukemia (AML) associated with complete monosomy 7 (−7) or deletion of the long arm of chromosome 7 (7q−). Patients with therapy-induced disease were excluded. The morphologic diag...
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Context 1
... 0.12) in −7 other, 0% in 7q−, and 35% 45,XX,−5,der(7)del(7)(p21)del(7)(q22q33),−9,der(9)t(5;9)(q22;q34),dup(13)(q12q14),+mar 720 AML M7 46,XX,t(8;16)(p11;q13),add(9)(q34.3)/46,XX,del(7)(q22),t(8;16)(p11;q13) Table 6 Analyses of prognostic factors (Figure 3b). The difference was not statisti- cally significant. ...
Context 2
... all patients received AML therapy (Table 1). The overall survival at 3 and 5 years was 34%, being consider- ably lower, although not statistically significant, in those with −7 alone (Figure 3b). Four children (one 7q−, three −7) received autologous BMT, three died of relapse, patient 422 has remained in complete remission 4. year post autologous BMT. ...
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Citations
... Pediatric myelodysplastic syndromes (MDSs) are characterized by impaired hematopoiesis, peripheral blood (PB) cytopenias, hypocellular bone marrows (BMs), and frequent deletions involving chromosome 7 (chr7) (1) and are associated with unique genetic predispositions (2,3). Studies from our lab and others identified heterozygous germline mutations in SAMD9 (sterile α motif domain-containing 9) and its paralog, SAMD9L, in 8% to 20% of primary pediatric MDS patients with deletions of chr7 (4,5). ...
SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death. Here we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. Using a range of in vivo and ex vivo assays, we showed that cells with heterozygous Samd9l mutations have impaired stemness relative to wild-type counterparts, which was exacerbated by inflammatory stimuli, and ultimately led to bone marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-β as a potential targetable pathway. Further, we observed non-random genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking chromosome 7 deletions observed in patients. Collectively, our study has enhanced our understanding of mutant Samd9l hematopoietic phenotypes, emphasized the synergistic role of inflammation in exaggerating the associated hematopoietic defects, and provided insights into potential therapeutic options for patients.
... JMML is a clonal hematopoietic stem cell disorder of childhood. It is extremely rare with an incidence rate of about 1 per 1 000 000 children under the age of 14 years (12,37,38,96). Like CMML the disease is characterized by proliferation of the monocytic lineage. ...
The WHO-category Myelodysplastic/Myeloproliferative neoplasms (MDS/MPNs) recognizes a unique group of clonal myeloid malignancies exhibiting overlapping features of myelodysplastic as well as myeloproliferative neoplasms. The group consists of chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR-ABL1-negative (aCML), juvenile myelomonocytic leukemia (JMML), myelodysplastic/myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U). The most frequent entity in this category is CMML, while all other diseases are extremely rare. Thus, only very limited data on the epidemiology of these subgroups exists. An appropriate diagnosis and classification can be challenging since the diagnosis is still largely based on morphologic criteria and myelodysplastic as well as myeloproliferative features can be found in various occurrences. The diseases in this category share several features that are common in this specific WHO-category, but also exhibit specific traits for each disease. This review summarizes published data on epidemiological features and offers a brief overview of the main diagnostic criteria and clinical characteristics of the five MDS/MPN subgroups.
... Favorable-risk genetics such as inv (16), t (8;21), and CEBPA and NPM1 mutations may be cured with chemotherapy alone [4][5][6]. In contrast, monosomy 7 and monosomy 5 or 5q deletions are high-risk (HR) features which require SCT in first remission for the best outcomes [7,8]. Rearrangements of KMT2A, located on chromosome 11q23, were also included in initial WHO classifications, but the prognostic significance was unclear until recently [9, 10••]. ...
Purpose of Review
Acute myeloid leukemia (AML) in children remains a challenging disease to cure with suboptimal outcomes particularly when compared to the more common lymphoid leukemias. Recent advances in the genetic characterization of AML have enhanced understanding of individualized patient risk, which has also led to the development of new therapeutic strategies. Here, we review key cytogenetic and molecular features of pediatric AML and how new therapies are being used to improve outcomes.
Recent Findings
Recent studies have revealed an increasing number of mutations, including WT1 , CBFA2T3 - GLIS2 , and KAT6A fusions, DEK - NUP214 and NUP98 fusions, and specific KMT2A rearrangements, which are associated with poor outcomes. However, outcomes are starting to improve with the addition of therapies such as gemtuzumab ozogamicin and FLT3 inhibitors, initially developed in adult AML.
Summary
The combination of advanced risk stratification and ongoing improvements and innovations in treatment strategy will undoubtedly lead to better outcomes for children with AML.
... Monosomy 7 (À7) or the partial deletion of the long arm of chromosome 7 (7qÀ) is a recurrent chromosomal aberration in myeloid-lineage haematological malignancies, such as myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML). [1][2][3] The presence of À7/7qÀ is known to be associated with poor prognosis, and generally stem cell transplantation (SCT) is required for treatment. [4][5][6] Since the recognition of 'monosomy 7 syndrome', 7 numerous researchers have attempted to find its underlying pathologic mechanism. ...
Monosomy 7 (−7) occurs in various types of paediatric myeloid disorders and has a poor prognosis. Recent studies have demonstrated that patients with germline gain‐of‐function SAMD9/9L variants and loss‐of‐function GATA2 variants are prone to developing myelodysplastic syndrome (MDS) associated with −7. However, the prevalence of the genetic variants among paediatric haematologic disorders with −7 is unknown. The present study screened germline variants of GATA2 and SAMD9/9L in 25 patients with various types of paediatric haematological disorders associated with −7. The diagnoses of the 25 patients included MDS (n = 10), acute myeloid leukaemia (AML) and myeloid sarcomas (n = 9), juvenile myelomonocytic leukaemia (n = 3) and other disorders (n = 3). Seven patients with a germline pathogenic GATA2 variant were found. For SAMD9/9L screening, next‐generation sequencing was used to detect low‐abundance variants and found four novel germline variants. Functional analysis revealed that three out of the four variants showed growth‐restricting capacity in vitro and thus, were judged to be pathogenic. Cases with GATA2 mutation tended to be older, compared to those with SAMD9/9L mutations. In conclusion, GATA2 and SAMD9/9L were sequenced in 25 patients with paediatric haematologic disorders associated with −7, and 40% of them were found to have some pathogenic germline variants in the three genes.
... As with the other MPNs in this category, the fi nal diagnosis is based on the exclusion of the BCR-ABL1 fusion [ 67 ] . The most common abnormality is −7/del(7q) and less frequently del(5q) [ 55,194,195 ] . ...
The knowledge that cancer is a malignant form of uncontrolled growth has existed for over a century. Several biological, chemical, and physical agents have been implicated in cancer causation. However, the mechanisms responsible for this uninhibited proliferation, following the initial insult(s), are still object of intense investigation. The first documented studies of cancer were performed over a century ago on domestic animals. At that time, the lack of both theoretical and technological knowledge impaired the formulations of conclusions about cancer, other than the visible presence of new growth, thus the term neoplasm (from the Greek neo = new and plasma = growth).
... Monosomy 7 is the most common chromosomal aberration in MDS [2][3][4][5][6]. It implies a rather poor prognosis that is associated with high risk of transformation to acute leukemia [7]. ...
... Complete loss of chromosome 7 (monosomy 7) or partial deletion involving its long arm [del(7q)] are highly recurrent chromosomal aberrations in myeloid disorders, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and juvenile myelomonocytic leukemia (JMML). 1,2 The International Prognostic Scoring System (IPSS), the most validated score for predicting the evolution of patients with MDS, does not discriminate among chromosome 7 anomalies, uniformly assigning these patients to the poor-risk karyotype group. 3 Other metaphase cytogenetic (MC) studies have consistently associated lesions involving the long arm of chromosome 7 with inferior survival in AML cases. ...
Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features.
... Families with several members affected with MDS often show monosomy 7 (Passmore et al, 1995; Hasle et al, 1999a; Owen et al, 2008). It is uncertain whether monosomy 7 per se increases the risk for familial MDS. ...
... Some patients present with slight hepatosplenomegaly but most have no organomegaly. Extramedullary myeloid tumour may be the presenting sign of advanced MDS with monosomy 7 (Hasle et al, 1999a; Hicsönmez et al, 2001) but blasts in the cerebrospinal fluid is not a feature of MDS. ...
... The outcome for patients with monosomy 7 is similar to that of other children with MDS but very poor for the few patients with monosomy 7 in combination with structural abnormalities (Hasle et al, 1999a; Woods et al, 2001; Luna- Fineman et al, 1999; Woods et al, 2002; Göhring et al, 2010). Monosomy 7 is a poor prognostic factor for adults with MDS (Greenberg et al, 1997) but is prognostic neutral in paediatric MDS. ...
Advanced myelodysplastic syndrome (MDS) in children includes refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T) according to the paediatric modification of the World Health Organization classification. Clinical features and cytogenetics are essential to make a diagnosis because blast count alone is insufficient to differentiate MDS from acute myeloid leukaemia (AML). Little is known about molecular genetics in paediatric MDS but hypermethylation seem to be frequent. Monosomy 7 is the most common cytogenetic aberration but prognostic neutral whereas those with structural complex karyotype have a very poor outcome. Haematopoietic stem cell transplantation (HSCT) is the treatment of choice and results in cure rates of around 60%. Intensive chemotherapy prior to HSCT provides no survival benefit for children with RAEB and RAEB-T and can generally not be recommended. Intensive chemotherapy before HSCT should be considered in patients with myelodysplasia-related-AML (MDR-AML).
... AML with chromosomal 7 aberrations represent a heterogeneous group; frequently are associated to others chromosomal aberrations, forming a complex karyotype. Monosomy 7 and deletion of 7q are present as single chromosomal alteration only in 35% and 33% respectively of all AML cases with chromosome 7 aberrations [62]. ...
Cytogenetic abnormalities are found in 50-60% of newly diagnosed acute myeloid leukemia (AML) of adult patients. Cytogenetic analysis of bone marrow leukemic cells is an important pre-treatment evaluation for a correct prognostic stratification of patients, that permit to separate AML patients in three broad prognostic categories: high, intermediate and low risk. The determination of cytogenetic features of AML remains a corner stone in predicting outcome although today its use needs to be integrated by molecular and immunophenotypic data, particularly in cytogenetically normal (CN) group of patients. In this review we perform a concise description of more recurrent cytogenetic aberrations found in AML, theirs correlations with biological and clinical data and theirs strong impact with outcome of patients, useful for therapeutic decision.
... The major diagnostic groups within MDS encountered in pediatric patients include JMML, myeloid leukemia of Down syndrome, and MDS occurring de novo and secondary to previous therapy or pre-existing disorders136137138. In general, pediatric MDS carries a poor prognosis and clinical variables have little practical utility in guiding therapy139140141142. ...
... In general, therapeutic options are limited in MDS and outcome is guarded. Some patients with MDS initially have an indolent course without therapy [141]. AML-type chemotherapy is associated with low response and high relapse rates [135,142]. ...
Leukemia represents the most common pediatric malignancy, accounting for approximately 30% of all cancers in children less than 20 years of age. Most children diagnosed with leukemia are cured without hematopoietic stem cell transplantation (HSCT), but for some high-risk subgroups, allogeneic HSCT plays an important role in their therapeutic approach. The characteristics of these high-risk subgroups and the role of HSCT in childhood leukemias are discussed.
