Objective: To investigate the genetic and genomic profiling of juvenile myelomonocytic leukemia (JMML) and factors affecting its survival rate. Methods: Clinical characteristics, cytogenetics, molecular biology results and survival status of children with 27 JMML cases admitted to the Hematology Department of Children's Hospital, Capital Institute of Pediatrics from December 2012 to December 2021 were analyzed retrospectively, and the outcomes of the children were followed up. Kaplan-Meier method was used for survival analysis. Univariate analysis was used for analyzing factors affecting the overall survival (OS) rates of patients who received hematopoietic stem cell transplantation (HSCT). Log-Rank test was used for comparison of survival curves. Results: Among 27 JMML cases, there were 11 males and 16 females. The age of disease onset was 28 (11,52) months. There are 20 cases of normal karyotype, 4 cases of monosomy 7, 1 case of trisomy 8,1 case of 11q23 rearrangement and 1 case of complex karyotype. A total of 39 somatic mutations were detected.Those involved in RAS signal pathway were the highest (64%(25/39)), among which PTPN11 mutation was the most frequent (44% (11/25)). A total of 17 cases (63%) received HSCT, 8 cases (30%) did not receive HSCT, and 2 cases (7%) lost follow-up. For children receiving transplantation, the follow-up time after transplantation was 47 (11,57) months. The 1-year OS rate of high-risk transplantation group (17 cases) and high-risk non transplantation group (6 cases) was (88±8)% and (50±20)% respectively, with a statistically significant difference (χ²=5.01, P=0.025). The 5-year OS rate of the high-risk transplantation group was (75±11)%. The survival time of those who relapsed or progressed to acute myeloid leukemia after transplantation was significantly shorter than that of those who did not relapse (χ²=6.80, P=0.009). The OS rate of patients with or without PTPN11 mutation was (81±12) % and (67±19)% respectively (χ²=0.85, P=0.356). Conclusions: The main pathogenesis involved in JMML is gene mutation related to RAS signaling pathway, and the most common driver gene of mutation is PTPN11. Allogeneic HSCT can significantly improve the survival rate of high-risk JMML patients. The recurrence or progression after transplantation was related to poor prognosis.
Male ; Female ; Child ; Humans ; Child, Preschool ; Leukemia, Myelomonocytic, Juvenile/therapy* ; Retrospective Studies ; Survival Analysis ; Mutation ; Hematopoietic Stem Cell Transplantation

OBJECTIVES: To investigate the clinical features of juvenile myelomonocytic leukemia (JMML) and their association with prognosis. METHODS: Clinical and prognosis data were collected from the children with JMML who were admitted from January 2008 to December 2016, and the influencing factors for prognosis were analyzed. RESULTS: A total of 63 children with JMML were included, with a median age of onset of 25 months and a male/female ratio of 3.2∶1. JMML genetic testing was performed for 54 children, and PTPN11 mutation was the most common mutation and was observed in 23 children (43%), among whom 19 had PTPN11 mutation alone and 4 had compound PTPN11 mutation, followed by NRAS mutation observed in 14 children (26%), among whom 12 had NRAS mutation alone and 2 had compound NRAS mutation. The 5-year overall survival (OS) rate was only 22%±10% in these children with JMML. Of the 63 children, 13 (21%) underwent hematopoietic stem cell transplantation (HSCT). The HSCT group had a significantly higher 5-year OS rate than the non-HSCT group (46%±14% vs 29%±7%, P<0.05). There was no significant difference in the 5-year OS rate between the children without PTPN11 gene mutation and those with PTPN11 gene mutation (30%±14% vs 27%±10%, P>0.05). The Cox proportional-hazards regression model analysis showed that platelet count <40×10⁹/L at diagnosis was an influencing factor for 5-year OS rate in children with JMML (P<0.05). CONCLUSIONS The PTPN11 gene was the most common mutant gene in JMML. Platelet count at diagnosis is associated with the prognosis in children with JMML. HSCT can improve the prognosis of children with JMML.
Child ; Humans ; Male ; Female ; Child, Preschool ; Leukemia, Myelomonocytic, Juvenile/therapy* ; Prognosis ; Genetic Testing ; Mutation ; Hematopoietic Stem Cell Transplantation

Humans ; Leukemia, Myelomonocytic, Juvenile/therapy*

OBJECTIVE: To explore the clinical efficacy and safety of unrelated umbilical cord blood transplantation (UCBT) in the treatment of Juvenile myelomonocytic leukemia (JMML). METHODS: The clinical data of 5 children with JMML who were treated with unrelated UCBT from October 2011 to July 2019 were retrospectively analyzed. The age of onset for the five children (male) ranged from 0.4 to 5.0 years old, with a median age of 1.5 years old. All the patients received myeloablative conditioning regimen without ATG to whom cyclosporine A (CsA) with short-term mycophenolate mofetil (MMF) was given for GVHD prophylaxis. RESULTS: Four children acquired engraftment. One patient received secondary haploidentical hematopoietic stem cell transplantation because of the failure in the first unrelated UCBT. Grade Ⅲ to Ⅳ aGVHD occurred in 2 cases and was controlled, and none of the patients developed cGVHD. Three cases achieved long-time disease free survival，and no patient relapsed. CONCLUSION UCBT is an effective treatment for children with JMML.
Child ; Child, Preschool ; Cord Blood Stem Cell Transplantation ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Infant ; Leukemia, Myelomonocytic, Juvenile ; Male ; Retrospective Studies ; Transplantation Conditioning

OBJECTIVE: To analyze the gene mutations of children with juvenile myelomonocytic leukemia (JMML) and their correlation with clinical characteristics. METHODS: The genetic mutation results and clinical data of 19 children with JMML in Fujian from January 2015 to December 2018 were collected and analyzed retrospectively. According to the results of gene mutation, they were divided into PTPN11 gene mutation group and non-PTPN11 gene mutation group, and the clinical characteristics and prognosis of children with JMML between two groups were compared. RESULTS: Among the 19 children with JMML, 14 cases were male and 5 cases were female, and male/female ratio was 2.8∶1. The median age at diagnosis was 13(3-48) months, and 14 cases (73.68%) were less than 2 years old. Abdominal distension and pyrexia were the common initial symptoms, and all the children with JMML had splenomegaly. The median white blood cell count was 39.82(4.53-103.4)×10 CONCLUSION JMML is more common in male infancy and toddlerhood, and the main gene mutation types are PTPN11 and Ras mutations. Because the JMML children with PTPN11 mutations show particularly rapid disease progression, if there is no timely intervention, most children die in a short period of time. Therefore, early HSCT may improve the prognosis of the children with JMML.
Child ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; Infant ; Leukemia, Myelomonocytic, Juvenile/genetics* ; Male ; Mutation ; Prognosis ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics* ; Retrospective Studies

OBJECTIVE: To study the clinical and genetic features of juvenile myelomonocytic leukemia (JMML) and the association between genotype and prognosis. Methods The clinical data of 15 children who were diagnosed with JMML were collected. Next-generation sequencing was used to detect common gene mutations of JMML. RESULTS: The male/female ratio was 6.5:1, and the age of onset was 19 months (range 2-67 months). Of the 15 children, 11 (73%) experienced disease onset before the age of 4 years, with abdominal distension and pyrexia as initial symptoms. All children had hepatosplenomegaly and superficial lymphadenectasis, with a number of peripheral blood mononuclear cells of >1.0×10/L and a percentage of juvenile cells of 1%-7% in peripheral blood smear. The percentage of bone marrow blasts + juvenile cells was <20%, and the percentage of monoblasts + promonocytes was 1%-10%. Of the 15 children, 10 (67%) had a higher level of hemoglobin F than the normal level at the corresponding age, with the highest level of 62.5%. All 15 children had the absence of Philadelphia chromosome, and one child had chromosome 7 deletion. All 15 children had a negative result of BCR/ABL fusion gene detection. PTPN11 gene mutation was found in 5 children (33%), NF1 mutation in 4 children (27%), CBL mutation in 3 children (20%), and RAS mutation in 3 children (20%). No children received regular chemotherapy, and one child underwent hematopoietic stem cell transplantation. The median follow-up time of 15 children was 18 months (range 1-48 months). Among the 15 children, 8 died (among whom 4 had PTPN11 gene mutation, 3 had NF1 mutation, and 1 had RAS mutation) and 7 survived. The children with PTPN11 mutation had the worst prognosis and the highest mortality rate, and those with CBL or NRAS mutation had a relatively good prognosis. The level of hemoglobin F was negatively correlated with survival time (r=-7.21, P=0.002). CONCLUSIONS In children with JMML, the type of gene mutation is associated with prognosis. The children with PTPN11 mutation often have a poor prognosis, and those with CBL or NRAS mutation have a relatively good prognosis.
Adolescent ; Child ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myelomonocytic, Juvenile ; genetics ; Leukocytes, Mononuclear ; Male ; Mutation ; Prognosis

To date, hematopoietic stem cell transplantation (HSCT) is the only choice of therapy for most patients with juvenile myelomonocytic leukemia (JMML). Relapse remains a major problem. Approximately 90% of patients carry either somatic or germline mutations of genes participating in RAS signal transduction such as PTPN11, CBL, K-RAS, N-RAS, or NF1 in their leukemic cells, allowing an understanding of the molecular pathophysiology of JMLL and the development of novel drugs. As these genetic aberrations are mutually exclusive, the genetic change observed in JMML helps us to establish the diagnosis of JMML. Furthermore, the genetic abnormalities of JMML are an important prognostic factor, as the type of abnormality may determine disease progression. Recent studies have revealed a strong association between hypermethylation of some genes and already known poor prognostic factors such as older age, elevated fetal hemoglobin at diagnosis, and somatic mutation of PTPN11. These molecular characteristics may be the basis for a guideline to determine the treatment, especially when to proceed with HSCT. Recently, novel drugs have been used based on these molecular characteristics. 5-Azacitidine, an inhibitor of DNA methyltransferase and tipifarnib, a selective farnesyl transferase inhibitor, have been used to improve the outcome of JMML. In addition, drugs which inhibit the RAS signal transduction have been developed, which are less toxic and will improve outcome in the near future.
Diagnosis ; Disease Progression ; DNA ; Fetal Hemoglobin ; Germ-Line Mutation ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myelomonocytic, Juvenile* ; Recurrence ; Signal Transduction ; Transferases

OBJECTIVETo study the clinical and laboratory characteristics of juvenile myelomonocytic leukemia (JMML).

METHODSThe clinical characteristics and laboratory results were retrospectively analyzed in 10 children with newly diagnosed JMML. They were compared with those of 28 children with myelodysplastic syndrome (MDS) and 44 children with chronic myeloid leukemia (CML).

RESULTSCompared with the children with CML or MDS, the children with JMML had significantly higher rates of skin rashes, ecchymosis, and lymphadenectasis, a significantly lower serum cholinesterase (ChE) level, and a significantly higher fetal hemoglobin level (P<0.05). The white blood cell count of children with JMML was significantly higher than that of children with MDS, but significantly lower than that of children with CML (P<0.05). In addition, the myeloid/erythroid ratio and rate of dyshaematopoiesis were significantly lower in children with JMML than those in children with CML or MDS. The children with JMML had a significantly higher expression of mature monocyte marker CD14 than those with CML or MDS (P<0.05). The levels of myeloid markers CD33, CD11b, CD13, and CD15 in children with JMML were significantly higher than those in children with MDS, but significantly lower than those in children with CML (P<0.05). The levels of CD2 and CD7 in children with JMML were higher than those in children with CML, but lower than those in children with MDS (P<0.05).

CONCLUSIONSSkin rashes, ecchymosis, lymphadenectasis, and ChE reduction are more common in children with JMML than in those with CML or MDS, while dyshaematopoiesis is less common. In addition, CD14 level increases significantly in children with JMML.

Child ; Child, Preschool ; Female ; Humans ; Infant ; Leukemia, Myelomonocytic, Juvenile ; genetics ; immunology ; Lipopolysaccharide Receptors ; analysis ; Male

Juvenile myelomonocytic leukemia (JMML) is a rare chronic myeloid leukemia in children and has the features of both myelodysplastic syndrome and myeloproliferative neoplasm. It is highly malignant and has a poor treatment outcome. Children with JMML have a poor response to conventional chemotherapy. At present, hematopoietic stem cell transplantation is the only possible cure for this disease. In recent years, significant progress has been made in targeted therapy for mutant genes in the Ras signaling pathway and demethylation treatment of aberrant methylation of polygenic CpG islands. This article reviews the treatment and efficacy evaluation of JMML.
Child ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myelomonocytic, Juvenile ; Methylation ; Myelodysplastic Syndromes ; Signal Transduction

OBJECTIVETo study gene mutations and clinical features in children with juvenile myelomonocytic leukemia (JMML).

METHODSThe clinical data of 14 children who were diagnosed with JMML and were examined for the detection of common gene mutations were retrospectively analyzed.

RESULTSEleven (79%) out of 14 cases were male, and 3 (21%) were female. The median age at diagnosis was 2.0 years (age range: 0.6-6.0 years). Among 14 cases, there were 4 cases (29%) with PTPN11 mutation, 3 cases (21%) with N-RAS mutation, 1 case (7%) with PTPN11 mutation and K-RAS mutation, and 6 cases (43%) without any mutation. All four cases in the PTPN11 mutation group were male, and their median age was 2.5 years; interval from onset to diagnosis was 1.0 month; the white blood cell (WBC) count and absolute monocytes in peripheral blood were significantly higher, while the platelet (PLT) count was lower, as compared with the other three groups; they were followed up, and 3 cases died and 1 case had a progressive disease. In the N-RAS mutation group, there were two male cases and one female case, and their median age was 2.0 years; interval from onset to diagnosis was 13.7 months; after follow-up, 2 cases died and 1 case did not have an obviously progressive disease.

CONCLUSIONSPTPN11 mutation is the most common mutation in JMML. The cases with PTPN11 mutation often have higher WBC count and absolute monocytes in peripheral blood, a lower PLT count, and a rapid disease progression, and their clinical outcomes are poor. The cases with N-RAS mutation have a slow disease progression. The clinical characteristics of the patients with compound mutations are not sure because of the small number of cases, and further clinical observation is indispensable.

Child ; Child, Preschool ; Female ; Genes, ras ; Humans ; Infant ; Leukemia, Myelomonocytic, Juvenile ; blood ; genetics ; Male ; Mutation ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; genetics ; Retrospective Studies