Childhood Myelodysplastic Syndrome: Focus on the Approach to Diagnosis and Treatment of Juvenile Myelomonocytic Leukemia

Loh, Mignon L.

doi:10.1182/asheducation-2010.1.357

Cited by 32 publications

(30 citation statements)

References 48 publications

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“…No data currently exist regarding the long-term outcome of such patients [3]. Our case supports the report by Matsuda et al of spontaneous remission in infants with JMML and NRAS Gly12Ser [2].…”

Section: Spontaneous Remission Of Jmml supporting

confidence: 93%

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Spontaneous Remission of Juvenile Myelomonocytic Leukemia withNRASMutation

Alsultan

Khalifah

Alrabiaah

2012

Pediatric Hematology and Oncology

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We describe a 29-month-old boy who presented at 1 month of age because of fever and hepatosplenomegaly. He had no features related to neurofibromatosis-1, juvenile xanthogranuloma or Noonan syndrome. The initial complete blood count (CBC) showed a white blood cell (WBC) count of 67,430/uL, an absolute monocyte (AMC) count of 10,790/uL, a hemoglobin (Hb) level of 9.2 g/dL, and a platelet count of 142,000/uL with 4% blasts. Bone marrow morphology showed 100% cellularity with 12% blasts. Cytogenetic analysis revealed a normal 46,XY male karyotype with no clonal abnormality. FISH for the 7q31 deletion and the BCR/ABL fusion gene were negative. A skeletal survey, an echocardiogram, and brain MRI were unremarkable. Fetal hemoglobin (HbF) was 22% at 2 months of age and 1% at 11 months. Testing for GM-CSF hypersensitivity of myeloid progenitors was not available.Juvenile myelomonocytic leukemia (JMML) molecular testing was performed on DNA extracted from unseparated peripheral blood leukocytes at Dr. Loh Lab (University of California, San Francisco). Our patient was found to have a heterozygous NRAS mutation at codon 12 of exon 1, causing amino acid change from glycine to serine (Gly12Ser). Therefore, our patient met the criteria for the diagnosis of JMML [1]. Testing for this mutation was not performed in other cells, e.g., fibroblasts so it is not possible to determine whether this mutation is constitutional or not. He has no human leukocyte antigen (HLA) matched related donor. The child continued to improve clinically with a marked reduction in the sizes of the spleen and liver and a decrease in the WBC and AMC counts (Figure 1). Given the lack of an HLA-matched sibling and the reported occurrence of spontaneous remission in JMML in infants with the Gly12Ser NRAS mutation [2], we continued to observe him with no therapeutic intervention. His most recent CBC showed 12,900 WBCs/uL, 1500 AMCs/uL, Hb level of 11.2 g/dL, and a platelet count of 446,000/uL with no peripheral blasts.Most clinicians adopt a universal approach toward the treatment of JMML. However, the molecular-based risk stratification of JMML patients might be more predictive of the long-term outcome [3]. Our patient has a heterozygous NRAS Gly12Ser mutation and JMML. His chronic leukemia spontaneously regressed with no treatment over a follow-up duration of more than 2 years. A similar observation

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Section: Spontaneous Remission Of Jmml supporting

confidence: 93%

“…However, the molecular-based risk stratification of JMML patients might be more predictive of the long-term outcome [3]. Our patient has a heterozygous NRAS Gly12Ser mutation and JMML.…”

mentioning

confidence: 85%

Spontaneous Remission of Juvenile Myelomonocytic Leukemia withNRASMutation

Alsultan

Khalifah

Alrabiaah

2012

Pediatric Hematology and Oncology

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“…Several genes of this superfamily have been found to be mutated in patients with myelodysplasia, including NRAS, KRAS, NF1, PTPN11, and CBL. Somatic or germ-line mutations of RAS pathway gene are present in ;90% of patients with juvenile CMML, 71 an MDS/MPN in which secondary mutations of SETBP1 and JAK3 may cause disease progression.…”

Section: Somatic Mutations In Other Cellular Pathwaysmentioning

confidence: 99%

The genetic basis of myelodysplasia and its clinical relevance

Cazzola¹,

Porta

Malcovati³

2013

Blood

310

299

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Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ≥1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in ≥10% MDS patients, whereas a long tail of ∼50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient’s genome are now needed.

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“…Juvenile Myelomonocytic Leukemia JMML is a rare, but highly aggressive, myeloid malignancy of childhood (54)(55)(56). JMML can be a difficult diagnosis to make, as many patients present with nonspecific clinical features that mimic infections or other conditions.…”

Section: Sequence Analysis Of Relapsed Acute Lymphoblastic Leukemiamentioning

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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Childhood Myelodysplastic Syndrome: Focus on the Approach to Diagnosis and Treatment of Juvenile Myelomonocytic Leukemia

Cited by 32 publications

References 48 publications

Spontaneous Remission of Juvenile Myelomonocytic Leukemia withNRASMutation

Spontaneous Remission of Juvenile Myelomonocytic Leukemia withNRASMutation

The genetic basis of myelodysplasia and its clinical relevance

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

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