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Concept: Juvenile myelomonocytic leukemia

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Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) that is refractory to conventional chemotherapy. Conditional inactivation of the Nf1 tumor suppressor in hematopoietic cells of mice causes a progressive MPN that accurately models JMML and chronic myelomonocytic leukemia (CMML). We characterized the effects of Nf1 loss on immature hematopoietic populations and investigated treatment with the MEK inhibitor PD0325901 (hereafter called 901). Somatic Nf1 inactivation resulted in a marked expansion of immature and lineage-committed myelo-erythroid progenitors and ineffective erythropoiesis. Treatment with 901 induced a durable drop in leukocyte counts, enhanced erythropoietic function, and markedly reduced spleen sizes in mice with MPN. MEK inhibition also restored a normal pattern of erythroid differentiation and greatly reduced extramedullary hematopoiesis. Remarkably, genetic analysis revealed the persistence of Nf1-deficient hematopoietic cells, indicating that MEK inhibition modulates the proliferation and differentiation of Nf1 mutant cells in vivo rather than eliminating them. These data provide a rationale for performing clinical trials of MEK inhibitors in patients with JMML and CMML.

Concepts: Cancer, Oncology, Red blood cell, Hematology, Leukemia, Spleen, Erythropoiesis, Juvenile myelomonocytic leukemia

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Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. Somatic mutations in genes involved in GM-CSF signal transduction, such as NRAS, KRAS, PTPN11, NF1, and CBL, have been identified in more than 70% of children with JMML. In the present study, we report 2 patients with somatic mosaicism for oncogenic NRAS mutations (G12D and G12S) associated with the development of JMML. The mutated allele frequencies quantified by pyrosequencing were various and ranged from 3%-50% in BM and other somatic cells (ie, buccal smear cells, hair bulbs, or nails). Both patients experienced spontaneous improvement of clinical symptoms and leukocytosis due to JMML without hematopoietic stem cell transplantation. These patients are the first reported to have somatic mosaicism for oncogenic NRAS mutations. The clinical course of these patients suggests that NRAS mosaicism may be associated with a mild disease phenotype in JMML.

Concepts: DNA, Gene, Genetics, Cancer, Mutation, Evolution, Hematology, Juvenile myelomonocytic leukemia

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Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of young children initiated by mutations that deregulate cytokine receptor signaling. Studies of JMML are constrained by limited access to patient tissues. We generated induced pluripotent stem cells (iPSCs) from malignant cells of two JMML patients with somatic heterozygous p.E76K missense mutations in PTPN11, which encodes SHP-2, a non-receptor tyrosine phosphatase. In vitro differentiation of JMML iPSCs produced myeloid cells with increased proliferative capacity, constitutive activation of granulocyte-macrophage colony stimulating factor (GM-CSF) and enhanced STAT5/ERK phosphorylation, similar to primary JMML cells from patients. Pharmacological inhibition of MEK kinase in iPSC-derived JMML cells reduced their GM-CSF independence, providing rationale for a potential targeted therapy. Our studies offer renewable sources of biologically relevant human cells in which to explore the pathophysiology and treatment of JMML. More generally, we illustrate the utility of iPSCs for in vitro modeling of a human malignancy.

Concepts: Cancer, Oncology, Signal transduction, Stem cell, Stem cells, Cell biology, Induced pluripotent stem cell, Juvenile myelomonocytic leukemia

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Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

Concepts: DNA, Genetics, Cancer, Molecular biology, Leukemia, Acute myeloid leukemia, Blood disorders, Juvenile myelomonocytic leukemia

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Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. NS also is associated with a risk for developing myeloproliferative disorders (MPD), including juvenile myelomonocytic leukemia (JMML). Mutations responsible for NS occur in at least 11 different loci including KRAS. Here we describe a mouse model for NS induced by K-Ras(V14I), a recurrent KRAS mutation in NS patients. K-Ras(V14I)-mutant mice displayed multiple NS-associated developmental defects such as growth delay, craniofacial dysmorphia, cardiac defects, and hematologic abnormalities including a severe form of MPD that resembles human JMML. Homozygous animals had perinatal lethality whose penetrance varied with genetic background. Exposure of pregnant mothers to a MEK inhibitor rescued perinatal lethality and prevented craniofacial dysmorphia and cardiac defects. However, Mek inhibition was not sufficient to correct these defects when mice were treated after weaning. Interestingly, Mek inhibition did not correct the neoplastic MPD characteristic of these mutant mice, regardless of the timing at which the mice were treated, thus suggesting that MPD is driven by additional signaling pathways. These genetically engineered K-Ras(V14I)-mutant mice offer an experimental tool for studying the molecular mechanisms underlying the clinical manifestations of NS. Perhaps more importantly, they should be useful as a preclinical model to test new therapies aimed at preventing or ameliorating those deficits associated with this syndrome.

Concepts: Genetics, Cancer, Genetic disorder, Mutation, Leukemia, Congenital heart defect, Noonan syndrome, Juvenile myelomonocytic leukemia

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Overactive RAS signaling is prevalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) in humans, and both are refractory to conventional chemotherapy. Conditional activation of a constitutively active oncogenic Nras (NrasG12D/G12D) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML-initiating cells, show strong hyperactivation of ERK1/2, promoting hyperproliferation and depletion of HSCs and expansion of downstream progenitors. Inhibition of the MEK pathway alone prolonged the presence of NrasG12D/G12D-expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of NrasG12D/G12D mice treated with MEK inhibitor alone died within 20 weeks, and the remaining animals continued to display JMML/MP-CMML-like phenotypes. In contrast, combined inhibition of MEK and JAK/STAT signaling, which is commonly hyperactivated in human and mouse CMML, potently inhibited human and mouse CMML cell growth in vitro, rescued mutant NrasG12D/G12D-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in NrasG12D/G12D animals. These results provide a strong rationale for further exploration of combined targeting of MEK/ERK and JAK/STAT in treating patients with JMML and MP-CMML.

Concepts: Gene, Cancer, Human, In vivo, Leukemia, In vitro, Mouse, Juvenile myelomonocytic leukemia

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Juvenile myelomonocytic leukemia (JMML) is a clonal hematopoietic disorder of infancy/early childhood, resulting from oncogenic mutations in genes involved in the Ras pathway. As JMML often exhibits an aggressive course, the timing of diagnosis and treatment is critical to outcome. Areas covered: This review summarizes current approaches to diagnosis and treatment of JMML, highlighting most recent insights into genetic and epigenetic mechanisms underlying the disease, and providing an overview of novel potential therapeutic strategies. Expert Commentary: At present, allogeneic HSCT remains the only potentially effective therapy, being able to cure more than 50% of patients, relapse representing the main cause of treatment failure. Prompt HSCT is recommended for all children with NF1, somatic PTPN11 and KRAS mutations, and for most children with somatic NRAS mutations. Conversely, a “watch and wait” strategy should be adopted in children with germline CBL mutations, specific somatic NRAS mutation, and in Noonan syndrome patients, since spontaneous resolution has been reported to occur. Novel drugs targeting relevant nodes of JMML leukemogenesis have been explored in pre-HSCT window or at relapse. The use of 5-azacytidine, a DNA-hypomethylating agent reported to induce hematologic and molecular remission in some JMML children, is currently being investigated in clinical trials.

Concepts: Genetics, Cancer, Hematology, Leukemia, Blood disorders, Noonan syndrome, Juvenile myelomonocytic leukemia

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Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

Concepts: DNA, Genetics, Gene expression, Mutation, Evolution, Histone, Methylation, Juvenile myelomonocytic leukemia

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Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in JMML vary markedly from spontaneous resolution to rapid relapse after hematopoietic stem cell transplantation. Here, we hypothesized that DNA methylation patterns would help predict disease outcome and therefore performed genome-wide DNA methylation profiling in a cohort of 39 patients. Unsupervised hierarchical clustering identifies three clusters of patients. Importantly, these clusters differ significantly in terms of 4-year event-free survival, with the lowest methylation cluster having the highest rates of survival. These findings were validated in an independent cohort of 40 patients. Notably, all but one of 14 patients experiencing spontaneous resolution cluster together and closer to 22 healthy controls than to other JMML cases. Thus, we show that DNA methylation patterns in JMML are predictive of outcome and can identify the patients most likely to experience spontaneous resolution.

Concepts: DNA, Prediction, Hematology, Leukemia, DNA methylation, Hematopoietic stem cell, Juvenile myelomonocytic leukemia

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Myelodysplasia (MDS) /myeloproliferative neoplasm (MPN) overlap syndrome has been described since the 2001 WHO classification as disorders that have both proliferative and dysplastic changes simultaneously. Specific disorders include chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), BCR-ABL negative atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MPN/MDS-U). Recurrent gene mutations in these conditions have been described. Among them, SETBP1 mutations have been identified in up to 32% of aCML, 24% of JMML, 18% of CMML and 10% of MDS/MPN-U patients. The mutation hotspot lies in the amino acid residues 858-871 in the SETBP1 protein. SETBP1 mutations in MDS/MPN overlap syndrome is associated with accelerated transformation to leukemia and poor prognosis. In this review, we summarized the latest data on the role of SETBP1 mutations in the overlap syndrome. SETBP1 mutations may serve as a biomarker for the diagnosis and poor prognosis of the overlap syndrome.

Concepts: Cancer, Mutation, Amino acid, Leukemia, Acute myeloid leukemia, Blood disorders, Myelodysplastic syndrome, Juvenile myelomonocytic leukemia