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.

C-Cbl but Not TET2 Mutations Are Present in Patients with Juvenile Myelomonocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 420-420 ◽  
Author(s):  
Hideki Muramatsu ◽  
Hideki Makishima ◽  
Anna Malgorzata Jankowska ◽  
Heather Cazzolli ◽  
Christine O'Keefe ◽  
...  
Keyword(s):  
Copy Number ◽  
Significant Proportion ◽  
High Density ◽  
Juvenile Myelomonocytic Leukemia ◽  
Kras Mutations ◽  
Hemoglobin F ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Gm Csf ◽  
Myelomonocytic Leukemia

Abstract Abstract 420 Juvenile myelomonocytic leukemia (JMML) is a distinct subtype of myelodysplastic syndrome/myeloproliferative disorder (MDS/MPD) which, in analogy to chronic myelomonocytic leukemia (CMML), is characterized by excessive proliferation of myelomonocytic cells, but unlike CMML it occurs in young children and shows characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Chromosomal defect are present in 22% of patients in particular involving del7/7q. Mutations of genes involved in GM-CSF signal transduction, including RAS and PTPN11, can be identified in a majority of children with JMML, constitutional mutations of NF1 can be found in another 10% of patients with JMML, but in significant proportion of patients no molecular lesions were identified. To further clarify the molecular pathogenesis of JMML we have applied a high density SNP array-based karyptyping and screened for associated mutations including established defected in RAS, PTPN11 and NF1 but also c-Cbl and TET genes, recently identified in patients with CMML and MDS/MPD. We studied 49 children with JMML diagnosed between 1988 and 2008 in 28 institutions throughout Japan. The median age at diagnosis was 28 months (range, 1-75 months). Karyotypic abnormalities were detected in 11 patients, including 7 patients with monosomy 7. Two children had clinical evidence of NF1 mutations. Out of 49 patients, 32 received hematopoietic stem cell transplantation (HSCT). We performed mutational analysis of the genes known to be affected by mutations in JMML. PTPN11 mutations were found in 26/49 (53%) while NRAS and KRAS mutations were found in 2/49 (4%) and 1/49 (2%), respectively. None of the patients screened showed the presence of TET2 mutations, previously shown to be present in a significant proportion of patients with MDS/MPD, including CMML. High-density Affymetrix 250K single nucleotide polymorphism array (SNP-A) were applied as a karyotyping platform to identify LOH and submicroscopic copy number changes. Signal intensity was analyzed and SNP calls determined using Gene Chip Genotyping Analysis Software Version 4.0 (GTYPE). Copy number and areas of UPD were investigated using Hidden Markov Model and CNAG v3.0 software. Compared to the results of conventional metaphase cytogenetics (MC), SNP-A identified significantly more genetic abnormalities (25% vs 49%; p=.02). In 1 patient UPD17q was present ivolving NF1 locus. In 4 patients UPD11q involving c-cbl locus (11q23.1) was found. Sequencing of c-Cbl gene family revealed mutations of c-Cbl in 5/49 (10%), and no Cbl-b mutations. All but 1 mutations were homozygous and were located in the RFD (exon 8 and intron 8). C-Cbl mutations were mutually exclusive with PTPN11, NRAS, and KRAS mutations or had clinical diagnosis of NF1. Unlike in CMML, no UPD4q24 or homo- or heterozygous TET2 mutations were found. Histomorphologic analysis did not reveal any distinct c-Cbl mutation-associated features or differences in count between patients grouped based on the presence of specific mutations. Similarly, there were no differences in gender, or the presence of cytogenetic abnormalities and the probability of 2 year overall survival of c-Cbl mutant cases between patients grouped according to mutational status. All patients with c-Cbl mutations displayed GM-CSF hypersensitivity at initial presentation but did not differ in this feature from the remaining JMML patients. However, mutant c-Cbl cases showed earlier presentation (median age 12 months vs. 29 months, p = .037) and lower median hemoglobin F fraction (3.5 % vs. 25%, p=.02). In sum, c-Cbl mutations constitute a novel important pathogenic lesion in JMML. While their presence suggests functional similarity to CMML, absence of TET2 mutation in JMML and rarity of PTPN11 mutations in CMML constitute important distinctive features of both diseases. Disclosures: No relevant conflicts of interest to declare.

A Favorable Outcome In Children with Juvenile Myelomonocytic Leukemia (JMML) with RAS Mutations

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2909-2909 ◽  
Author(s):  
Sayoko Doisaki ◽  
Hideki Muramatsu ◽  
Asahito Hama ◽  
Akira Shimada ◽  
Yoshiyuki Takahashi ◽  
...  
Keyword(s):  
Platelet Count ◽  
Juvenile Myelomonocytic Leukemia ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Ras Mutations ◽  
Gm Csf ◽  
Ras Genes ◽  
Hbf Level ◽  
Myelomonocytic Leukemia

Abstract Abstract 2909 Introduction: Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder that affects young children. It is characterized by a specific hypersensitivity of JMML cells to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. The pathogenesis of JMML involves disruption of GM-CSF signal transduction resulting from mutations of the components of the RAS signaling pathway, including NF1, PTPN11, NRAS, and KRAS. Somatic point mutations of the RAS genes at codons 12, 13, and 61 are found in approximately 20% of patients. Although most patients with JMML die due to progressive disease within 12 months unless treated with hematopoietic stem cell transplantation (HSCT), Matsuda et al reported that JMML patients with NRAS or KRAS glycine to serine substitution improved spontaneously. Other groups in Europe did not confirm this observation, and treatment for patients with JMML and RAS mutations is controversial. Therefore, in the present study, we analyze the association between the mutational status of RAS and prognoses of patients with JMML. Patients and Methods: Eighty children diagnosed with JMML between 1988 and 2010 were studied retrospectively. We performed a mutational analysis of NRAS, KRAS, PTPN11, and C-CBL genes. Results: Seventeen patients (21%) had RAS mutations [NRAS (n = 13) and KRAS (n = 4)], while PTPN11 and C-CBL mutations were found in 28 patients (35%) and 5 patients (6.3%), respectively (Four patients were included in the previous report; Matsuda et al, Blood, 2007). Five children had clinical evidence of NF1 mutations. Among NRAS mutations, G12D and G13D were the most common (n = 6 and n = 5, respectively). Only one patient carried a G12S substitution, which was reported as a favorable mutation. Three patients with KRAS mutations had G13D substitutions. Compared to patients with other mutations or without any aberrations, patients with RAS mutations were significantly younger at diagnosis (median age: 12 months vs. 24 months, p = 0.011), while other known predictive factors such as HbF level and platelet count were not significantly different at diagnosis (median HbF level: 9.1 % vs. 22.2 %, p = 0.295; median platelet count: 27.5 × 109/L vs. 49.0 × 109/L, p = 0.390). Monosomy 7 was observed in seven patients without RAS mutations, and all patients with RAS mutations had normal karyotypes. Among untransplanted patients with RAS mutations, three achieved long-term survival (20, 84, and 209 months after diagnosis). The probability of 5-year overall survival estimated by the Kaplan-Meier method was significantly higher for patients with RAS mutations than for those without (85.7% vs. 30.4%, p = 0.033). Conclusion: These results suggest that JMML patients with RAS mutations may be a distinct subgroup with favorable outcomes in spite of other than G12S. 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.

scholarly journals Correlation of Clinical Features With the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Juvenile Myelomonocytic Leukemia

2009 ◽  
Vol 65 (3) ◽  
pp. 334-340 ◽  
Author(s):  
Nao Yoshida ◽  
Hiroshi Yagasaki ◽  
Yinyan Xu ◽  
Kazuyuki Matsuda ◽  
Ayami Yoshimi ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Clinical Features ◽  
Juvenile Myelomonocytic Leukemia ◽  
Gm Csf ◽  
Mutational Status ◽  
Myelomonocytic Leukemia

Rapamycin -- a Potential Mechanistically Targeted Therapeutic for Juvenile Myelomonocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2378-2378
Author(s):  
Y. Lucy Liu ◽  
Robert P. Castleberry ◽  
Peter Dean Emanuel
Keyword(s):  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Juvenile Myelomonocytic Leukemia ◽  
Ras Signaling ◽  
Sensitivity Testing ◽  
Blood Concentrations ◽  
Patient Sample ◽  
Gm Csf ◽  
Myelomonocytic Leukemia

Abstract Juvenile myelomonocytic leukemia (JMML) is a mixed myelodysplastic /myeloproliferative disorder (MDS/MPD) of infancy and early childhood. It is characterized by monocytosis, leukocytosis, elevated fetal hemoglobin, hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a low percentage of myeloblasts in the bone marrow, and absence of the Philadelphia chromosome or the BCR/ABL fusion gene. The pathogenesis of JMML has been clearly and definitively linked to dysregulated signal transduction through the RAS signaling pathway. A series of studies conducted over the last decade have shown that mutations or other abnormalities in RAS, NF1, and PTPN11, are potentially responsible for the pathogenesis of JMML in up to 75% of cases. Treatment has been very difficult. There is no effective therapy for JMML. Only allogeneic stem cell transplantation (SCT) can extend survival. However, the relapse rate from allogeneic SCT is inordinately high in JMML (28–55%), with 5-year disease-free survival rates of 25-40%. Rapamycin is a macrolide antibiotic with established clinical applications in organ transplantation. Recent studies have proved that the Mammalian Target of Rapamycin (mTOR) plays an important role in cytokine receptor signaling and induction of apoptosis. Numerous studies have suggested that mTOR functions as a nutritional checkpoint and is connected to energy sensing through AMP-dependent kinase (AMPK) which senses the AMP: ATP ratio in cells. Its function is regulated by the RAS/PI3-kinase pathway. In searching for novel mechanistically-targeted reagents to treat JMML, we conducted an in vitro pilot study with JMML cells. The CFU-GM formation assay was used to test the therapeutic sensitivity of rapamycin to JMML cells. Mononuclear cells (MNCs) from peripheral blood of 9 JMML patients were collected and plated on 0.3% agar medium with rapamycin at a concentration of 1-8nM(0.91-7.28μg/L) and carrier (DMSO). Greater than 50% inhibition of spontaneous CFU-GM growth was observed in all cultures in a dose-dependent fashion, with the exception of one patient sample which had colonies resistant to rapamycin. The effective concentrations in our cultures are equivalent to the safe and tolerable whole blood concentrations achieved in organ transplant patients in clinical settings (5-30μg/L). Our data suggests that rapamycin may be considered as a potentially safe and effective reagent to treat JMML, but that in vitro sensitivity testing might be recommended since one patient sample demonstrated complete resistance to rapamycin in vitro. Further studies are ongoing to explore the mechanism of rapamycin in inhibiting hypersensitivity of JMML cells to GM-CSF.

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.

Correlation of Clinical Features with the Mutational Status of GM-CSF Signaling Pathway-Related Genes in Children with Juvenile Myelomonocytic Leukemia

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1528-1528 ◽  
Author(s):  
Nao Yoshida ◽  
Hiroshi Yagasaki ◽  
Ayami Yoshimi ◽  
Yoshiyuki Takahashi ◽  
Yinyan Xu ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Clinical Outcome ◽  
Clinical Features ◽  
Juvenile Myelomonocytic Leukemia ◽  
Gm Csf ◽  
Ptpn11 Mutation ◽  
Mutational Status ◽  
Hbf Level ◽  
Mutation Age ◽  
Myelomonocytic Leukemia

Abstract Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder that affects young children. It is characterized by specific hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Mutations in RAS, NF1, or PTPN11 positioned in the GM-CSF signal pathway, are thought to be involved in the pathogenesis of JMML. However, no information is available on the relationship between these mutations and clinical features of JMML. The impacts of these mutations on clinical outcome also remain unclear. We tested 49 Japanese children with JMML for N-RAS, K-RAS, and PTPN11 mutations and evaluated their clinical significance. We also assessed correlations between mutational status and clinical and laboratory findings, including age at diagnosis, fetal hemoglobin (HbF), platelet count, and cytogenetic abnormality, all which have been proposed as prognostic factors for JMML. Of the 49 JMML patients, cytogenetic abnormalities were detected in 13, including 8 with monosomy 7. For 2 patients, a clinical diagnosis of neurofibromatosis type 1 (NF1) was confirmed. PTPN11 and N-/K-RAS mutations were found in 22 (45%) and 8 (16%) patients, respectively. Neither PTPN11 nor RAS mutations nor NF1 were present in 17 (35%) patients, and no simultaneous aberrations in these genes were found. In patients with the PTPN11 mutation, age at diagnosis was older (35 vs 11 months; P=0.001, or 12 months; P<0.01) and HbF level was higher (31 vs 10%; P=0.03, or 16%; P<0.01) than for patients with the RAS mutation or without any aberration, suggesting that the clinical outcome for patients with the PTPN11 mutation might be poorer, because a higher HbF level and older age have been reported to be poor prognostic factors. In fact, overall survival (OS) at 5 years was lower for patients with the PTPN11 mutation than for those without (20±9% vs 58±9%; P=0.02). In addition to PTPN11 mutation, age older than 24 months (P<0.01) and abnormal karyotype (P=0.02) were also associated with poor prognosis for OS. Of the 49 patients, 33 received stem cell transplantation (SCT). OS probabilities for patients with and without a mutation in PTPN11 at 5 years after SCT were 25±10% and 64±12%, respectively (P=0.04). More importantly, mutation in PTPN11 was the only unfavorable factor for relapse after SCT (P<0.01). Seven patients died owing to relapse and 12 from complications. All patients who died after relapse had a PTPN11 mutation. In summary, our results suggest that PTPN11-mutated JMML might be a distinct subgroup with specific clinical characteristics and a poor outcome.

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