scholarly journals Sustained fetal hematopoiesis causes juvenile death from leukemia: evidence from a dual-age–specific mouse model

2020 ◽  
Vol 4 (15) ◽  
pp. 3728-3740
Author(s):  
Nitza Vara ◽  
Yuqing Liu ◽  
Yan Yan ◽  
Shelly Y. Lensing ◽  
Natalia Colorado ◽  
...  
Keyword(s):  
Mouse Model ◽  
Feedback Loop ◽  
Mapk Pathway ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Pten Loss ◽  
Pten Deletion ◽  
Fetal Hematopoiesis ◽  
The Impact ◽  
Myelomonocytic Leukemia

Abstract It is not clear whether disrupted age-specific hematopoiesis contributes to the complex manifestations in leukemia patients who carry identical mutations, particularly in pediatric and adult patients with similar clinical characteristics. By studying a dual-age–specific mouse model, we demonstrate that (1) loss of Pten during the fetal-to-adult hematopoiesis switch (hematopoiesis switch) causes sustained fetal hematopoiesis, resulting in death in juvenile leukemia; (2) myeloid-biased hematopoiesis in juvenile mice is associated with the sustained fetal properties of hematopoietic stem cells (HSCs); (3) the age specificity of juvenile myelomonocytic leukemia depends on the copy number of Pten and Nf1; (4) single-allelic Pten deletion during the hematopoiesis switch causes constitutive activation of MAPK in juvenile mice with Nf1 loss of heterozygosity (LOH); and (5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that 1 copy of Pten is sufficient to maintain an intact negative-feedback loop of the Akt pathway and HSC function in reconstitution, despite MAPK being constitutively activated in juvenile Pten+/ΔNf1LOH mice. However, 2 copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. Our data indicate that previous investigations of Pten function in wild-type mice may not reflect the impact of Pten loss in mice with Nf1 mutations or other genetic defects. We provide a proof of concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise.

scholarly journals A Pediatric Case of Systemic Lupus Erythematosus Developed 10 Years after Cord Blood Transplantation for Juvenile Myelomonocytic Leukemia

2012 ◽  
Vol 2012 ◽  
pp. 1-4
Author(s):  
Masayuki Nagasawa ◽  
Yuki Aoki
Keyword(s):  
Cord Blood ◽  
Lupus Erythematosus ◽  
Cord Blood Transplantation ◽  
Juvenile Myelomonocytic Leukemia ◽  
Systemic Lupus ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Blood Transplantation ◽  
The Impact ◽  
Myelomonocytic Leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a most powerful immunotherapy for hematological malignancies. However, the impact of immunological disturbances as a result of allo-HSCT is not understood well. We experienced an 11-year-old boy who presented with systemic lupus erythemathosus (SLE) 10 years after unrelated cord blood transplantation of male origin for juvenile myelomonocytic leukemia (JMML) with monosomy 7. Bone marrow examination showed complete remission without monosomy 7. Genetic analysis of peripheral blood revealed mixed chimera with recipient cells consisting of <5% of T cells, 50–60% of B cells, 60–75% of NK cells, 70–80% of macrophages, and 50–60% of granulocytes. Significance of persistent mixed chimera as a cause of SLE is discussed.

scholarly journals Nf1 and Sh2b3 mutations cooperate in vivo in a mouse model of juvenile myelomonocytic leukemia

2021 ◽  
Author(s):  
Carolina E. Morales ◽  
Elliot Stieglitz ◽  
Scott C. Kogan ◽  
Mignon L. Loh ◽  
Benjamin S Braun
Keyword(s):  
Adverse Outcomes ◽  
Juvenile Myelomonocytic Leukemia ◽  
Ras Signaling ◽  
Hemoglobin F ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Increased Risk ◽  
Genetically Engineered Mice ◽  
The Impact ◽  
Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is initiated in early childhood by somatic mutations that activate Ras signaling. While some patients have only a single identifiable oncogenic mutation, others have one or more additional alterations. Such secondary mutations, as a group, are associated with an increased risk of relapse after hematopoietic stem cell transplantation, or transformation to acute myeloid leukemia. These clinical observations suggest a cooperative effect between initiating and secondary mutations. However, the roles of specific genes in the prognosis or clinical presentation of JMML have not been described. In this study, we investigate the impact of secondary SH2B3 mutations in JMML. We find that patients with SH2B3 mutations have adverse outcomes, as well as higher white blood cell counts and hemoglobin F levels in the peripheral blood. We further demonstrate this interaction in genetically engineered mice. Deletion of Sh2b3 cooperates with conditional Nf1 deletion in a dose-dependent fashion. These studies illustrate that haploinsufficiency for Sh2b3 contributes to the severity of myeloproliferative disease and provide an experimental system for testing treatments for a high-risk cohort of JMML patients.

scholarly journals The Dosage of Pten Is Critical in Determining the Disease Severity - a Mouse Model Differentially Mimicking JMML and CMML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1550-1550
Author(s):  
Yan Yan ◽  
Natalia C Colorado ◽  
Shelly Lensing ◽  
Delli R Robinson ◽  
Nicholas J Baltz ◽  
...  
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
Disease Severity ◽  
Age Of Onset ◽  
Juvenile Myelomonocytic Leukemia ◽  
Marginal Zone B Cells ◽  
Gm Csf ◽  
Pten Deletion ◽  
Myelomonocytic Cells ◽  
Myelomonocytic Leukemia

Abstract Juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML) are mixed myelodysplastic syndromes (MDS)/myeloproliferative neoplasms (MPNs) that share similar clinical manifestations, but differ in prognosis and ages at diagnosis. Both are characterized by monocytosis and monocytic infiltration in vital organs. JMML is extremely aggressive, with death occurring within one year after diagnosis in children (<6 Yrs) without therapy, whereas CMML presents in adults with a more indolent course. A dysregulated RAS pathway is the key mechanism of JMML and CMML, but the number of non-synonymous mutations per tumor in JMML patients is ranked among the least of all human cancers. Previously, we reported that mice with somatic Pten deletion and germline mutant Nf1 (PtenΔ/ΔNf1wt/-) mimic human MPNs with features of a pediatric mixed MDS/MPNs, in terms of age of onset and organ infiltration with myelomonocytic cells, but lack a key feature of JMML with respect to GM-CSF hypersensitivity (Blood 2016; 127:1912). In order to simulate the molecular dynamics observed in JMML, we introduced Nf1 Loss-Of-Heterozygosity (Nf1LOH) by somatically deleting the second copy of Nf1 in mice on postnatal day 8 (PND8, equivalent to a full-term newborn age in humans).We generated mice with PtenfloxP/floxPNf1Fcr/floxPMx1-Cre+on a C57BL6/129 genetic background, and conditionally deleted Pten and the second copy of Nf1 myeloid-specifically by intraperitoneal injection of Poly(I:C). Mice with bi-allelic Pten deletion and Nf1LOH (PtenΔ/ΔNf1LOH) were born healthy but revealed signs of sickness in the 2nd week of life, and all died by age 4 weeks (equivalent to 1-3 years old in humans); whereas mice with heterozygous Pten deletion and Nf1LOH (Pten wt/ΔNf1LOH) did not show obvious signs of disease until age 2 months, and possessed a lifespan longer than 3 months. The natural lifespan of PtenΔ/ΔNf1LOH mice (n=8) was significantly shorter than littermates with PtenΔ/ΔNf1wt/Δ (n=18), Pten wt/ΔNf1LOH(n=10), or wild type (ptenwtNf1wt, hereafter referred asWT, n=14, p<0.001). We analyzed 13 PtenΔ/ΔNf1LOH mice at age PND18-21 along withtheir littermates. Substantial hepatosplenomegaly was observed in mice with Pten deletion and correlated with the loss of copy number of Pten and Nf1 inthe following order: PtenΔ/ΔNf1LOH> PtenΔ/ΔNf1wt/Δ > Pten wt/ΔNf1LOH> WT (median spleen weight: 228>180>134>56mg, respectively, p<0.001). Mice with PtenΔ/ΔNf1LOH(n=13) or Pten wt/ΔNf1LOH(n=12) had significantly elevated white blood cells (WBCs) and a lower hemoglobin than PtenΔ/ΔNf1wt/Δ (n=21) or WT littermates (n=15). HE stained tissue sections of formalin-fixed organs revealed increased cellularity in bone marrow (BM), and severe infiltration of mature myeloid cells in the spleens, livers, and lungs of mice with PtenΔ/ΔNf1LOH. Flow cytometry analysis (FACS) revealed that PtenΔ/ΔNf1LOHmice had significantly increased monocyte/macrophages and granulocytes in BM and peripheral blood (PB), but significant reduction in T-cells and B-cells in PB and spleen. A significant increase in Ter119+CD71high cells was also found in PtenΔ/ΔNf1LOH mice, indicating MDS or leukemia. Interestingly, splenic marginal zone B-cells were significantly lower exclusively in PtenΔ/ΔNf1LOHmice. Mice with Ptenwt/ΔNf1LOHhad the similar FACS profile with less disease severity at age PND18-21. They lived longer than 3 months without obvious signs of disease except increased WBCs and mild anemia. BM cells from PtenΔ/ΔNf1LOH mice at an age of 3 weeks were hypersensitive to GM-CSF, but Ptenwt/ΔNf1LOH mice did not display this until an age of 2 months. Based on the Bethesda proposals for classification of non-lymphoid hematopoietic neoplasms in mice, we have developed a mouse model of a mixed MDS/MPNs with features of JMML and CMML, in terms of age of onset and organ infiltration with myelomonocytic cells, and GM-CSF hypersensitivity. In conclusion, our data demonstrate that bi-allelic Pten deletion and Nf1LOH at an early age results in JMML in mice, whereas single-allelic Pten deletion with Nf1LOH induces CMML. This is the first mouse model that differentially resembles pediatric and adult mixed MDS/MPNs, and closely mimics the true genetic and epigenetic dynamics in humans. It provides a novel tool for studying the mechanisms underlying pediatric and adult mixed MDS/MPNs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia

2021 ◽  
Vol 218 (2) ◽  
Author(s):  
Eleni Louka ◽  
Benjamin Povinelli ◽  
Alba Rodriguez-Meira ◽  
Gemma Buck ◽  
Wei Xiong Wen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Childhood Leukemia ◽  
Clonal Evolution ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Ras Pathway ◽  
Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin−CD34+CD38−CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a “first hit,” (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.

scholarly journals Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment

Leukemia ◽  
2019 ◽  
Vol 34 (6) ◽  
pp. 1658-1668
Author(s):  
Aurélie Caye ◽  
Kevin Rouault-Pierre ◽  
Marion Strullu ◽  
Elodie Lainey ◽  
Ander Abarrategi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Myeloproliferative Neoplasm ◽  
Juvenile Myelomonocytic Leukemia ◽  
Integrated Analysis ◽  
Cell Phenotype ◽  
Hematopoietic Stem ◽  
Activating Mutations ◽  
Colony Forming Assay ◽  
Myelomonocytic Leukemia

AbstractJuvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches.

scholarly journals Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1124-1127 ◽  
Author(s):  
Sophie Archambeault ◽  
Nikki J. Flores ◽  
Ayami Yoshimi ◽  
Christian P. Kratz ◽  
Miriam Reising ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Allele Specific ◽  
Myelomonocytic Leukemia

AbstractJuvenile myelomonocytic leukemia is an aggressive and frequently lethal myeloproliferative disorder of childhood. Somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases. Monitoring disease status is difficult because of the lack of characteristic leukemic blasts at diagnosis. We designed a fluorescently based, allele-specific polymerase chain reaction assay called TaqMAMA to detect the most common RAS or PTPN11 mutations. We analyzed peripheral blood and/or bone marrow of 25 patients for levels of mutant alleles over time. Analysis of pre–hematopoietic stem-cell transplantation, samples revealed a broad distribution of the quantity of the mutant alleles. After hematopoietic stem-cell transplantation, the level of the mutant allele rose rapidly in patients who relapsed and correlated well with falling donor chimerism. Simultaneously analyzed peripheral blood and bone marrow samples demonstrate that blood can be monitored for residual disease. Importantly, these assays provide a sensitive strategy to evaluate molecular responses to new therapeutic strategies.

Rapid Cyclosporine Tapering and Isotretinoin Usage after Unrelated Donor Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5188-5188
Author(s):  
Keon Hee Yoo ◽  
Soo Hyun Lee ◽  
Ki Woong Sung ◽  
Hong Hoe Koo ◽  
Hye Lim Jung
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Differentiating Agent ◽  
Myelomonocytic Leukemia ◽  
Disease Free

Abstract Juvenile myelomonocytic leukemia (JMML) is a rare type of childhood leukemias, and allogeneic hematopoietic stem cell transplantation (HSCT) is known to be the only way to cure the disease. Unfortunately, relapse is still the most frequent cause of treatment failure after transplant in JMML. We investigated the feasibility of inducing graft versus leukemia (GVL) effect and the use of a differentiating agent even after unrelated HSCT in children with JMML. Seven consecutive patients with JMML underwent unrelated HSCT at a median age of 17 months. The sources of grafts were bone marrows (n=3) or HLA 1- or 2-antigen mismatched cord bloods (n=4). Only 3 of the 7 patients were in complete remission before transplantation. Intravenous busulfan, cyclophosphamide, and etoposide were used as preparative agents except in one who was conditioned with TBI-based regimen. Cyclosporine was used universally for GVHD prophylaxis with additional use of short-term methotrexate in bone marrow transplants and of methyl-prednisolone in cord blood transplants. Cyclosporine was tapered rapidly from around 1 month post-HSCT and isotretinoin (75–100 mg/m2/day) was used in selected patients who have any risk factors of relapse. Cyclosporine blood levels were 247.8±91.1, 146.6±104.2, and 88.8±52.6 ng/mL at 1, 2, and 3 months post-transplant, respectively. There was no grade 3 or 4 acute GVHD and only 2 patients developed grade 2 acute GVHD which was improved without additional treatment. Chronic GVHD was developed in 3 (1 limited, 2 extensive) of the evaluable 5 patents, which was all resolved after combined use of immune suppressive agents. Initial chimeric status analysis at 1 month revealed complete donor chimerism (CC) in 4 patients, mixed chimerism (MC) in 2 and autologous recovery (AR) in one. One of the patients with MC and the one with AR were in disease-free status. One patient whose chimeric status changed from CC to MC eventually relapsed. One patient with initial MC with residual disease turned to CC with complete remission. Another patient with initial MC but with no evidence of disease is on treatment with isotretinoin without relapse for 3 months even with persistent MC. The patient with AR relapsed early after transplant. Five patients are alive relapse-free and disease-free with a median follow-up of 16 months after transplant. The Kaplan-Meier probability of event-free survival was 66.7%. We suggest that GVL induction strategy with concomittant use of a differentiating agent might have a role to suppress leukemic relapse in JMML.

Mutations In GATA2 Are Rare In Juvenile Myelomonocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1526-1526
Author(s):  
Elliot Stieglitz ◽  
Y. Lucy Liu ◽  
Peter D. Emanuel ◽  
Robert P. Castleberry ◽  
Todd Michael Cooper ◽  
...  
Keyword(s):  
Point Mutation ◽  
Trans Configuration ◽  
Juvenile Myelomonocytic Leukemia ◽  
Sequence Variants ◽  
Wild Type ◽  
Monosomy 7 ◽  
Atypical Features ◽  
The Impact ◽  
Myelomonocytic Leukemia ◽  
Chronic Neutropenia

Abstract Germline mutations in GATA2, a gene that encodes for transcription factors involved in hematopoiesis and vascular development, have recently been described in MonoMAC syndrome, Emberger syndrome and in select cases of mild chronic neutropenia. These disorders are unified by their predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Patients with MonoMAC syndrome have also been noted to display monosomy 7 in their bone marrows in up to 50% of cases. Overexpression of GATA2 due to somatic mutations in cases of de novo pediatric AML, has also been shown to be a negative predictor of outcome. Juvenile myelomonocytic leukemia is a rare childhood malignancy with overlapping features of MDS and myeloproliferative neoplasm (MPN) that can transform to AML and is characterized by hyperactive RAS signaling. Mutations in NF1, NRAS, KRAS, PTPN11, and CBL are found in 85-90% of newly diagnosed patients, and monosomy 7 is the most common recurrent karyotypic abnormality seen in JMML. We therefore hypothesized that mutations in GATA2 may play a role in the development of JMML. Samples from 57 patients with JMML were screened for GATA2 mutations. Patient samples and clinical data were collected from the Children's Oncology Group (COG) trial AAML0122. DNA was extracted as per previous protocols from peripheral blood or bone marrow and whole genome amplified using Qiagen REPLI-g kit according to manufacturer specifications. We performed bidirectional Sanger sequencing (Beckman Coulter Genomics) of the entire coding region of GATA2 (NM_001145661.1) and aligned the sequences using CLC Workbench software (CLC Bio, Aarhus, Denmark). Only missense, splice site or nonsense mutations were evaluated using SIFT (Sorting Tolerant From Intolerant) to predict the impact on the structure and function of identified mutations on the protein. Patient J384 was found to have a nonsense point mutation at c.988C>T (R330X) in the N-terminal region of the zinc finger portion of the protein (Figure 1a). This hotspot mutation has been reported in several patients with mild chronic neutropenia who displayed a predisposition to developing MDS and AML. The patient was also found to have a missense point mutation at c.962T>G (L321R) predicted to be damaging by SIFT. Subcloning of the gene using a TA cloning kit with pCR 2.1 vector (Invitrogen), followed by direct sequencing of individual colony picks, revealed that the two sequence variants only occurred in a trans configuration. Out of 40 amplicons sequenced, 20 were found to have the c.988C>T transition, 16 were found to be have the c.962T>G variant, and four were found to be wild type. We therefore hypothesize that the c.988C>T was inherited as a germline event and that c.962T>G was somatically acquired in the majority of the remaining wild type alleles. No other point mutations or insertions/deletions were discovered in this cohort.Figure 1Identification of 2 distinct GATA2 mutations in patient J384.Figure 1. Identification of 2 distinct GATA2 mutations in patient J384. This patient was previously identified to have a KRAS G12D mutation (c.35G>A) as well as monosomy 7. This patient died prior to undergoing transplant within months of diagnosis. While the patient technically met criteria for the diagnosis of JMML, it should be noted there were several atypical features, including older age at diagnosis (4 years and 10 months), and absence of hypersensitivity in myeloid progenitor cells to the cytokine granulocyte–macrophage colony stimulating factor (GM-CSF) in colony assay. This raises the possibility that patient J384 actually had MonoMAC syndrome with MDS and not JMML. This represents the first description of a GATA2 mutation in a patient suspected of having JMML. To our knowledge, this is the first report of a biallelic mutation in GATA2, combining a germline mutation with somatic acquisition. In addition, MonoMAC syndrome has not been reported to be associated with KRAS mutations to date. GATA2 mutations should therefore be considered in patients with atypical features of MDS or JMML. Panel (a) Bidirectional sequencing of patient sample J384 revealed two distinct sequence variants in both the forward (shown here) and reverse strands. Panel (b) Sequencing of 40 individual colony picks revealed that each sequence variant occurred in a trans configuration (CP 9 and CP13 are shown here as examples). In addition, 10% of colony picks (i.e. CP 32) revealed a wild type sequence, indicating that at least one of the two variants was a somatic event. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia

Blood ◽  
2012 ◽  
Vol 120 (7) ◽  
pp. 1485-1488 ◽  
Author(s):  
Sayoko Doisaki ◽  
Hideki Muramatsu ◽  
Akira Shimada ◽  
Yoshiyuki Takahashi ◽  
Makiko Mori-Ezaki ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Somatic Mosaicism ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Mild Disease ◽  
Myeloid Neoplasm ◽  
Buccal Smear ◽  
Spontaneous Improvement ◽  
Myelomonocytic Leukemia

Abstract 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.

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