RESUMEN
Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs. Built on these findings, we showed that JAK inhibitor (JAKi) significantly reduced aberrant HSPCs and mitigated leukemia development in a mouse model of aggressive myeloid leukemia driven by loss of Cbl and Cbl-b Importantly, primary human CBL mutated (CBLmut ) leukemias exhibited increased JAK2 protein levels and signaling and were hypersensitive to JAKi. Loss-of-function mutations in CBL E3 ubiquitin ligases are found in a wide range of myeloid malignancies, which are diseases without effective treatment options. Hence, our studies reveal a novel signaling axis that regulates JAK2 in normal and malignant HSPCs and suggest new therapeutic strategies for treating CBLmut myeloid malignancies.
Asunto(s)
Janus Quinasa 2/metabolismo , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/fisiopatología , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Citocinas/metabolismo , Estabilidad de Enzimas , Células Madre Hematopoyéticas/enzimología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Janus Quinasa 2/genética , Leucemia Mieloide Aguda/genética , Proteínas de la Membrana , Ratones , Mutación , Proteolisis , Proteínas Proto-Oncogénicas c-cbl/genética , Transducción de Señal/genética , UbiquitinaciónRESUMEN
Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1.
Asunto(s)
Leucemia Mielomonocítica Juvenil , Neurofibromatosis 1 , Niño , Humanos , Leucemia Mielomonocítica Juvenil/genética , Neurofibromatosis 1/genética , Mutación , Transducción de Señal , Genes Supresores de TumorRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm of childhood. The molecular hallmark of JMML is hyperactivation of the Ras/MAPK pathway with the most common cause being mutations in the gene PTPN11, encoding the protein tyrosine phosphatase SHP2. Current strategies for treating JMML include using the hypomethylating agent, 5-azacitidine (5-Aza) or MEK inhibitors trametinib and PD0325901 (PD-901), but none of these are curative as monotherapy. Utilizing an Shp2E76K/+ murine model of JMML, we show that the combination of 5-Aza and PD-901 modulates several hematologic abnormalities often seen in JMML patients, in part by reducing the burden of leukemic hematopoietic stem and progenitor cells (HSC/Ps). The reduced JMML features in drug-treated mice were associated with a decrease in p-MEK and p-ERK levels in Shp2E76K/+ mice treated with the combination of 5-Aza and PD-901. RNA-sequencing analysis revealed a reduction in several RAS and MAPK signaling-related genes. Additionally, a decrease in the expression of genes associated with inflammation and myeloid leukemia was also observed in Shp2E76K/+ mice treated with the combination of the two drugs. Finally, we report two patients with JMML and PTPN11 mutations treated with 5-Aza, trametinib, and chemotherapy who experienced a clinical response because of the combination treatment.
Asunto(s)
Leucemia Mielomonocítica Juvenil , Animales , Ratones , Azacitidina/farmacología , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/uso terapéutico , Mutación , Inhibidores de Proteínas Quinasas , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , HumanosRESUMEN
Juvenile myelomonocytic leukaemia (JMML) is an aggressive paediatric leukaemia characterized by mutations in five canonical RAS pathway genes, including the NF1 gene. JMML is driven by germline NF1 gene mutations, with additional somatic aberrations resulting in the NF1 biallelic inactivation, leading to disease progression. Germline mutations in the NF1 gene alone primarily cause benign neurofibromatosis type 1 (NF1) tumours rather than malignant JMML, yet the underlying mechanism remains unclear. Here, we demonstrate that with reduced NF1 gene dose, immune cells are promoted in anti-tumour immune response. Comparing the biological properties of JMML and NF1 patients, we found that not only JMML but also NF1 patients driven by NF1 mutations could increase monocytes generation. But monocytes cannot further malignant development in NF1 patients. Utilizing haematopoietic and macrophage differentiation from iPSCs, we revealed that NF1 mutations or knockout (KO) recapitulated the classical haematopoietic pathological features of JMML with reduced NF1 gene dose. NF1 mutations or KO promoted the proliferation and immune function of NK cells and iMacs derived from iPSCs. Moreover, NF1-mutated iNKs had a high capacity to kill NF1-KO iMacs. NF1-mutated or KO iNKs administration delayed leukaemia progression in a xenograft animal model. Our findings demonstrate that germline NF1 mutations alone cannot directly drive JMML development and suggest a potential cell immunotherapy for JMML patients.
Asunto(s)
Leucemia Mielomonocítica Juvenil , Neurofibromatosis 1 , Animales , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Leucemia Mielomonocítica Juvenil/metabolismo , Neurofibromina 1/genética , Genes de Neurofibromatosis 1 , Mutación de Línea Germinal , Neurofibromatosis 1/genética , Neurofibromatosis 1/terapia , Mutación , Inmunidad , Células Germinativas/metabolismo , Células Germinativas/patologíaRESUMEN
BACKGROUND: Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III. AIM: To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III. METHODS: This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients. RESULTS: The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/µL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS). CONCLUSION: In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.
Asunto(s)
Síndrome de Deficiencia de Adhesión del Leucocito , Osteopetrosis , Humanos , Masculino , Femenino , Osteopetrosis/diagnóstico , Osteopetrosis/genética , Síndrome de Deficiencia de Adhesión del Leucocito/diagnóstico , Síndrome de Deficiencia de Adhesión del Leucocito/genética , Integrinas/fisiología , Leucocitos/metabolismo , Leucocitos/patologíaRESUMEN
BACKGROUND: CBL syndrome is a RASopathy caused by heterozygous germline mutations of the Casitas B-lineage lymphoma (CBL) gene. It is characterized by heterogeneous clinical phenotype, including developmental delay, facial dysmorphisms, cardiovascular malformations and an increased risk of cancer development, particularly juvenile myelomonocytic leukemia (JMML). Although the clinical phenotype has been progressively defined in recent years, immunological manifestations have not been well elucidated to date. METHODS: We studied the genetic, immunological, coagulative, and clinical profile of a family with CBL syndrome that came to our observation after the diagnosis of JMML, with homozygous CBL mutation, in one of the members. RESULTS: Variant analysis revealed the co-occurrence of CBL heterozygous mutation (c.1141 T > C) and SH2B3 mutation (c.1697G > A) in two other members. Patients carrying both mutations showed an ALPS-like phenotype characterized by lymphoproliferation, cytopenia, increased double-negative T-cells, impaired Fas-mediated lymphocyte apoptosis, altered cell death in PBMC and low TRECs expression. A coagulative work-up was also performed and showed the presence of subclinical coagulative alterations in patients carrying both mutations. CONCLUSION: In the reported family, we described immune dysregulation, as part of the clinical spectrum of CBL mutation with the co-occurrence of SH2B3.
Asunto(s)
Leucemia Mielomonocítica Juvenil , Proteínas Proto-Oncogénicas c-cbl , Células Germinativas/metabolismo , Mutación de Línea Germinal/genética , Humanos , Leucemia Mielomonocítica Juvenil/complicaciones , Leucemia Mielomonocítica Juvenil/genética , Leucocitos Mononucleares/metabolismo , Proteínas Proto-Oncogénicas c-cbl/genética , Proteínas Proto-Oncogénicas c-cbl/metabolismoRESUMEN
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton's tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment.
Asunto(s)
Leucemia Mielomonocítica Juvenil , Trombocitopenia , Agammaglobulinemia Tirosina Quinasa/genética , Animales , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/metabolismo , Leucemia Mielomonocítica Juvenil/terapia , Ratones , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Esplenomegalia/genética , Células Madre/metabolismoRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive clonal neoplasm of early childhood, classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization. In 90% of the patients with JMML, typical initiating mutations in the canonical Ras pathway genes NF1, PTPN11, NRAS, KRAS, and CBL can be identified. Hematopoietic stem cell transplantation (HSCT) currently is the established standard of care in most patients, although long-term survival is still only 50-60%. Given the limited therapeutic options and the important morbidity and mortality associated with HSCT, new therapeutic approaches are urgently needed. Hyperactivation of the Ras pathway as disease mechanism in JMML lends itself to the use of targeted therapy. Targeted therapy could play an important role in the future treatment of patients with JMML. This review presents a comprehensive overview of targeted therapies already developed and evaluated in vitro and in vivo in patients with JMML.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Juvenil , Síndromes Mielodisplásicos , Preescolar , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/metabolismo , Leucemia Mielomonocítica Juvenil/terapia , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Therapy-related myeloid neoplasms (t-MN) are a distinct subgroup of myeloid malignancies with a poor prognosis that include cases of therapy-related myelodysplastic syndrome (t-MDS), therapy-related myeloproliferative neoplasms (t-MPN) and therapy-related acute myeloid leukemia (t-AML). Here, we report a series of patients with clinical features consistent with juvenile myelomonocytic leukemia (JMML), an overlap syndrome of MDS and myeloproliferative neoplasms that developed after treatment for another malignancy.
Asunto(s)
Leucemia Mielomonocítica Juvenil , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Neoplasias Primarias Secundarias , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/terapia , Síndromes Mielodisplásicos/inducido químicamente , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Neoplasias Primarias Secundarias/diagnósticoRESUMEN
Although several types of chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) targeting myeloid antigens have been developed for acute myeloid leukemia (AML) globally, significant clinical benefits have not yet been reported. Furthermore, CAR-T cells targeting juvenile myelomonocytic leukemia (JMML) have not yet been developed. All JMML cells and 63-83% of AML cells express granulocyte macrophage-colony stimulating factor (GM-CSF) receptor (GMR, CD116/CD131 complex). Therefore, we created ligand-based CAR-T cells targeting GMR using the piggyBac transposon system. We further redesigned the CAR construct by optimizing the affinity of the antigen-binding region and length of the spacer region. The GMR CAR-T cells with a mutated GM-CSF at residue 21 (E21K) and a G4S spacer showed superior antitumor effects in the human AML-xenograft model. Safety tests revealed that the toxicity of GMR CAR-T cells was restricted to normal monocytes. Based on the promising results of the nonclinical study, we started a first-in-human clinical trial of GMR CAR-T cells in patients with CD116-positive AML and JMML in 2021.
Asunto(s)
Leucemia Mieloide Aguda , Leucemia Mielomonocítica Juvenil , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos , Linfocitos TRESUMEN
BACKGROUND: Inflammatory manifestations (IM) are well described in adult patients with myelodysplastic syndrome (MDS), but the presentation is highly variable and no standardized treatment exists. This phenomenon is rarely reported in children. As more pediatric patients are hematopoietic stem cell transplantation (HSCT) candidates, the role of anti-inflammatory treatment in relation to HSCT should be defined. PROCEDURE: Here, we report a series of five children from a tertiary center. We describe the clinical presentation, molecular findings, and treatment options. RESULTS: All patients presented with advanced MDS with blast percentages ranging 10-30%, all had severe IM. One patient had MDS secondary to severe congenital neutropenia, the other four patients had presumably primary MDS. All four were found to harbor a PTPN11 gene driver mutation, which is found in 35% of cases of juvenile myelomonocytic leukemia (JMML). The mutation was present in the myeloid lineage but not in T lymphocytes. Three had symptoms of Behcet's-like disease with trisomy 8 in their bone marrow. All patients were treated with anti-inflammatory medications (mainly systemic steroids) in an attempt to bring them to allogeneic HSCT in a better clinical condition. All demonstrated clinical improvement as well as regression in their MDS status post anti-inflammatory treatment. All have recovered from both MDS and their inflammatory symptoms post HSCT. CONCLUSION: Primary pediatric MDS with IM is driven in some cases by PTPN11 mutations, and might be on the clinical spectrum of JMML. Anti-inflammatory treatment may reverse MDS progression and improve the outcome of subsequent HSCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Juvenil , Síndromes Mielodisplásicos , Niño , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Resultado del Tratamiento , TrisomíaRESUMEN
BACKGROUND: HSCT is the only proven curative therapy for JMML. Matching donor and recipient HLA alleles is considered optimal to reduce the risk of GVHD after HSCT but is not always possible. Only a limited number of studies have compared the influence of HLA disparities on HSCT outcomes for patients with JMML. METHODS: We conducted a retrospective study among 47 children with JMML who received related or unrelated unmanipulated HSCT (March 2010-October 2018). Among our participants, 27 (57.4%) donor-recipient pairs had 0-1 HLA disparities (Group 1: HLA-matched or ≤1 allele/antigen mismatch donor) and 20 (42.6%) had ≥2 HLA disparities (Group 2: 2-3 mismatched/haploidentical donors). RESULTS: The median follow-up period was 26.0 months (range: 1-105 months), and the 5-year probabilities of DFS and RI for the whole cohort were 54.6 ± 7.7% and 34.8 ± 15.0%, respectively. Compared to Group 1, Group 2 patients had a significantly lower RI (5.3 ± 10.5% vs 55.5 ± 20.9%, P Ë .001), though similar rates of grade II-IV acute GVHD (60.0 ± 22.4% vs 33.3 ± 18.2%, P = .08), grade III-IV acute GVHD (25.0 ± 19.5% vs 7.4 ± 10.1%, P = .08), chronic GVHD (30.0 ± 20.9% vs 34.9 ± 18.8%, P = .85), NRM (20.0 ± 18.0% vs 3.9 ± 7.7%, P = .07), and DFS (74.4 ± 9.9% vs 41.3 ± 10.0%, P = .08). CONCLUSIONS: Disease relapse remains the major cause of treatment failure in JMML patients, especially in patients receiving HLA-matched and limited HLA-mismatched HSCT. Our findings suggest that donor-recipient HLA disparities may improve the outcome of HSCT in children with JMML.
Asunto(s)
Selección de Donante , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Prueba de Histocompatibilidad , Leucemia Mielomonocítica Juvenil/terapia , Biomarcadores , Niño , Preescolar , China , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Lactante , Estimación de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/inmunología , Leucemia Mielomonocítica Juvenil/mortalidad , Masculino , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Prevención Secundaria , Donantes de Tejidos , Resultado del TratamientoRESUMEN
RUNX1 associated familial platelet disorder (FPD) is a rare autosomal dominant hematologic disorder characterized by thrombocytopenia and/or altered platelet function. There is an increased propensity to develop myeloid malignancy (MM) - acute myeloid leukemia, myeloproliferative neoplasms or myelodysplastic syndrome often in association with secondary somatic variants in other genes. To date, 23 FPD-MM pediatric cases have been reported worldwide. Here, we present two new kindreds with novel RUNX1 pathogenic variants in which children are probands. The first family is a daughter/mother diad, sharing a heterozygous frameshift variant in RUNX1 gene (c.501delT p.Ser167Argfs*9). The daughter, age 13 years, presented with features resembling juvenile myelomonocytic leukemia - severe anemia, thrombocytopenia, high white cell count with blast cells, monocytosis, increased nucleated red cells and had somatic mutations with high allele burden in CUX1, PHF6, and SH2B3 genes. She also had increased fetal hemoglobin and increased LIN28B expression. The mother, who had a long history of hypoplastic anemia, had different somatic mutations- a non-coding mutation in CUX1 but none in PHF6 or SH2B3. Her fetal hemoglobin and LIN28B expression were normal. In the second kindred, the proband, now 4 years old with thrombocytopenia alone, was investigated at 3 months of age for persistent neonatal thrombocytopenia with large platelets. Molecular testing identified a heterozygous intragenic deletion in RUNX1 encompassing exon 5. His father is known to have increased bruising for several years but is unavailable for testing. These two cases illustrate the significance of secondary mutations in the development and progression of RUNX1-FPD to MM.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Hemoglobina Fetal/genética , Leucemia Mieloide Aguda/genética , Adolescente , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Fenotipo , Estudios RetrospectivosRESUMEN
Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B-lymphoblast population which declined with similar kinetics as his JMML-associated abnormalities, suggesting that a B-lymphoblast population in JMML does not always progress to acute leukemia.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Células Precursoras de Linfocitos B/patología , Deleción Cromosómica , Cromosomas Humanos Par 7 , Humanos , Lactante , Leucemia Mielomonocítica Juvenil/patología , Masculino , Inducción de RemisiónRESUMEN
BACKGROUND: Despite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre-HCT therapy has an effect on the molecular burden of disease and how this affects outcome post-HCT. PROCEDURE: Twenty-one patients with JMML who received pre-HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre-HCT therapy, using custom amplicon next-generation sequencing. RESULTS: Of the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate-intensity chemotherapy, one patient received only azacitidine. The 5-year progression-free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of high-intensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre-HCT therapy. CONCLUSIONS: Despite the myelodysplastic nature of JMML, patients treated with pre-HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post-HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Genes Relacionados con las Neoplasias , Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Terapia Neoadyuvante , Análisis de Secuencia de ADN , Carga Tumoral/efectos de los fármacos , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Terapia Combinada , ADN de Neoplasias/sangre , Evaluación de Medicamentos , Monitoreo de Drogas , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/terapia , Humanos , Lactante , Leucemia Mielomonocítica Juvenil/sangre , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Proteínas de Neoplasias/genética , Supervivencia sin Progresión , Recurrencia , Estudios Retrospectivos , Esplenectomía , Acondicionamiento PretrasplanteRESUMEN
JMML is an aggressive hematopoietic malignancy of early childhood, and allogeneic HSCT is the only curative treatment for this disease. Umbilical cord blood is one of donor sources for HSCT in JMML patients who do not have an HLA-compatible relative, but engraftment failure remains a major problem. Here, we report two cases of JMML who were successfully rescued by HSCT from an HLA-mismatched parent after development of primary engraftment failure following unrelated CBT. Both patients had severe splenomegaly and underwent unrelated CBT from an HLA-mismatched donor. Immediately after diagnosis of engraftment failure, both patients underwent HSCT from their parent. For the second HSCT, we used RIC regimens consisting of FLU, CY, and a low dose of rabbit ATG with or without TBI and additionally administered ETP considering their persistent severe splenomegaly. Both patients achieved engraftment without severe treatment-related adverse effects. After engraftment of second HSCT, their splenomegaly was rapidly regressed, and both patients showed no sign of relapse for over 4 years. These observations demonstrate that HSCT from an HLA-mismatched parent could be a feasible salvage treatment for primary engraftment failure in JMML patients.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/citología , Leucemia Mielomonocítica Juvenil/terapia , Preescolar , Femenino , Sangre Fetal , Hepatomegalia/cirugía , Humanos , Inmunosupresores/uso terapéutico , Lactante , Masculino , Mutación , Recurrencia , Esplenomegalia/cirugía , Acondicionamiento Pretrasplante , Resultado del TratamientoRESUMEN
The WAS gene product is expressed exclusively in the cytoplasm of hematopoietic cells and constitutional genetic abrogation of WASP leads to Wiskott-Aldrich syndrome (WAS). Moreover, mutational activation of WASP has been associated with X-linked neutropenia. Although studies reported that patients with constitutional WAS mutations affecting functional WASP expression may present juvenile myelomonocytic leukemia (JMML)-like features, confounding differential diagnosis above all in the copresence of mutated RAS, an activating somatic mutation of WASP has not been previously described in JMML patients. In our ongoing studies on JMML genomics, we at first detected a somatic WAS mutation in a major clone found at two consecutive relapses in one of two twins with JMML. Both twins were treated with hematopoietic stem cell transplantation after diagnosis of JMML. The somatic WAS mutation detected here displayed an activating WASP phenotype. Screening of 46 sporadic JMML patients at disease onset for mutations in the same PBD domain of WAS revealed two additional singleton patients carrying minor mutated clones. This is the first study to associate somatically acquired WASP mutations with a hematopoietic malignancy and increases insight in the complexity of the genomic landscape of JMML that shows low recurrent mutations concomitant with general hyperactivation of RAS pathway signaling.
Asunto(s)
Mutación con Ganancia de Función , Leucemia Mielomonocítica Juvenil/genética , Proteína del Síndrome de Wiskott-Aldrich/genética , Proteínas ras/genética , Niño , Humanos , Masculino , Transducción de Señal/genéticaRESUMEN
Juvenile myelomonocytic leukemia (JMML), an invasive myeloproliferative neoplasm, is a childhood disease with very high clinical lethality. Somatic mutation E76K in SHP2 is the most commonly identified mutation found in up to 35% of patients with JMML. To investigate the effect of gain-of-function mutation-E76K on SHP2 activity, molecular dynamic simulations on the wild-type SHP2 (SHP2-WT) system and the mutated E76K (SHP2-E76K) system were performed. The evaluation of stability of these two systems indicated that the simulated trajectories were stable after simulation for 3 nanoseconds. The root mean square fluctuation and the per-residue root mean square deviation illustrated that there were two regions (residues Tyr 81-Glu 83 and Glu 258-Leu 261) in the wild-type system and the mutated system, which had large differences. The principal component analysis, dynamic cross correlation maps analysis, as well as secondary structure analysis suggested that the mutated E76K impacted the movement of these two regions in SHP2 protein. Furthermore, residue interaction network analysis, hydrogen bond occupancy, and binding free energies analysis were used to explain how the two regions were specifically affected by the mutant. The results indicated that the primary variances between SHP2-WT and SHP2-E76K were the different interactions between Glu/Lys 76 and Arg 265, Tyr 80 and Leu 77, Leu 77 and Tyr 81, Thr 73 and Glu 258, Ala 75 and Cys 259, Phe 71 and Tyr 81, Ala 75 and Glu 258, and Tyr 73 and Glu/Lys 76. Consequently, these findings here might provide insights into the increased activity in SHP2-E76K.
Asunto(s)
Mutación con Ganancia de Función , Leucemia Mielomonocítica Juvenil/genética , Simulación de Dinámica Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Humanos , Enlace de Hidrógeno , Mutación Missense , Conformación Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 11/química , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismoRESUMEN
Previous studies have reported several cases of juvenile myelomonocytic leukemia (JMML) developing blastic transformation during an indolent clinical course, but the underlying mechanism of transformation is still not well understood. In this report, we describe a case of JMML with blastic transformation possibly caused by additional copy number gains of the KRAS mutant allele. We have discovered that the copy number gain of the mutant allele is an additional possible cause of blastic transformation in JMML.
Asunto(s)
Dosificación de Gen , Leucemia Mielomonocítica Juvenil/genética , Activación de Linfocitos/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Trasplante de Médula Ósea , Femenino , Humanos , Lactante , Leucemia Mielomonocítica Juvenil/terapiaRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm with poor prognosis except in the setting of Noonan syndrome, where prognosis is generally favorable. We present the case of a child with JMML in the setting of germline PTPN11 mutation and Noonan syndrome with suspected secondary development of monosomy 7 in the bone marrow. Diagnosed shortly after birth, she has been managed with active surveillance alone. Myeloblast percentages initially fluctuated; however, bone marrow biopsy at 4 years of age showed spontaneous remission despite persistence of the monosomy 7 clone, supporting a cautious approach in similar cases.