scholarly journals Stem cell origins of JMML

2021 ◽  
Vol 218 (2) ◽  
Author(s):  
Sriram Sundaravel ◽  
Ulrich Steidl
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Progenitor Cell ◽  
Therapeutic Targets ◽  
Leukemia Stem Cells ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Cell Compartments ◽  
Myelomonocytic Leukemia

In this issue of JEM, Louka et al. (https://doi.org/10.1084/jem.20180853) report that leukemia stem cells lie within the phenotypic hematopoietic stem cell and progenitor cell compartments in juvenile myelomonocytic leukemia (JMML). Furthermore, they identify several candidate biomarker/therapeutic targets, such as CD96 and SLC2A1, that are of translational significance in JMML.

scholarly journals The results of hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia at the Russian Children’s Clinical Hospital

2019 ◽  
Vol 6 (2) ◽  
pp. 20-29
Author(s):  
E. V. Machneva ◽  
V. V. Konstantinova ◽  
Yu. V. Skvortsova ◽  
А. E. Burya ◽  
N. V. Sidorova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Juvenile Myelomonocytic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Myelomonocytic Leukemia

Relevance. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only effective treatment method for the majority of patients with juvenile myelomonocytic leukemia (JMML). The authors of the article presented the experience of conducting HSCT in patients with JMML in the Russian Children’s Clinical Hospital.Materials and methods. 55 HSCT for the period from 2003 to 2019 were performed in forty-two patients with JMML. 14 (33.3 %) patients from a related HLA-identical donor were given primary HSCT, 1 (2.4 %) from a related 9/10 HLA-compatible, 16 (38.1 %) – from unrelated HLA-identical, 6 (14.3 %) – from unrelated 9/10 HLA-compatible, 5 (11.9 %) – from haploidentical. The source of hematopoietic stem cells (HSC) in primary HSCT for 22 (52.4 %) patients was bone marrow (BM), for 13 (31.0 %) – peripheral blood stem cells (PBSC), for 4 (9.5 %) – cord blood (CB), for 3 (7.1 %) – BM in combination with CB. Twenty-two (52.4 %) patients received a myeloablative busulfan-containing conditioning regimen, 20 (47.6 %) – treosulfan-containing.Results. The overall survival (OS) of patients for the entire observation period was 53 ± 8.3 %; transplantation lethality (TL) – 21.2 ± 6.8 %, relapse-free survival (RFS) – 72.0 ± 7.7 %, event-free survival (EFS) – 49.4 ± 7.8 %. The factors negatively influencing the results of HSCT in patients with JMML were the progression of the underlying disease at the time of HSCT, incomplete compatibility of the HSC donor, the use of CB as a source of HSC.Conclusion. Indicators of OS, RFS, EFS patients with JMLL after HSCT are low. The reasons for treatment failure are TL, graft failure and relapse after transplantation. To improve the results of treatment of patients with JMML, careful selection of the donor and the source of HSC, the maximum possible reduction in the toxicity of conditioning regimens is necessary.

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 An Encouraging Successful Result of Allogeneic Hematopoietic Stem Cell Transplantation in a Boy Both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta : A Case Report

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Fang Liu ◽  
Xiaofan Zhu ◽  
Wenyu Yang ◽  
Ye Guo ◽  
Xia Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Osteogenesis Imperfecta ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Juvenile Myelomonocytic Leukemia ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia

Background: Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in young children that is classified as a myelodysplastic/myeloproliferative neoplasm and not only characterized by young age, hepatosplenomegaly, thrombocytopenia and monocytosis, but also by molecular aberrations in the RAS-RAF-MEK-ERK signaling pathway and GM-CSF-hypersensitivity. Most children with JMML experience an aggressive clinical course and the only curative treatment option for these children is stem cell transplantation (SCT). Osteogenesis imperfect (OI) is also an orphan inherited monogenic bone fragility disorder that usually is caused by mutations in one of the two genes coding for collagen type I alpha chains, COL1A1 or COL1A2. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities. Current multidisciplinary management could only improve quality of life for patients, including physical therapy, drug treatment and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell or bone marrow transplantation, targeting the specific altered pathway rather than the symptoms, may develop new curative treatments. Here we report a 3-year-old boy who suffered from both JMML and OI, was successfully transplanted and kept presenting an encouraging outcome up to now. Aims:To investigate the possible efficacy and safety of Allogeneic Hematopoietic Stem Cell Transplantation in a boy both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta. Methods:A 3-year-old boy presented with fatigue, fever, petechia and rash in Aug 2019, accompanying with loss of appetite, joint pain and severe hepatosplenomegaly. The boy had a special appearance of short stature and blue sclerae, meanwhile he suffered intermittent eczema and bone fracture twice since he was 2 years old. Similar characteristics were also positive in his grandmother, father and father's sister. The blood cell counts revealed anemia, thrombocytopenia and leukocytosis especially monocytosis. Bone marrow aspirate showed excessive proliferation of myelomonocytic cells and hypersensitivity to granulocyte-macrophage colony-stimulating factor in vitro. Somatic mutation of gene NF1, PTPN11 and COL1A1 were identified by Next Generation Sequencing.Therefore, the little boy was diagnosed with two rare diseases of Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta at the same time. After 4 courses of hypomethylating agents therapy, the boy underwent haploidentical allogeneic bone marrow stem cell transplantation combined with allogeneic single umbilical cord blood transplant in May 2020. The myeloablative conditioning regimen was composed of Decitabine (20mg/m2/day, days -13 to -9), Cyclophosphamide (25mg/kg/day, days -8 and -7), Busulfan(100mg/m2/day, days -6 to -3), Fludarabine (40mg/m2/day, days -6 to -2) and Cytarabine (100mg/m2/day, days -6 to -2). Post-Cyclophosphamide (50mg/kg/day, days +3 and +4), tacrolimus and mycophenolate mofetil were used for prophylaxis of graft-versus-host disease (GVHD). Results:The number of infused TNCs from haplo-bone marrow and cord blood unit was 41.4×10^8/kg and 9.72×10^7/kg, respectively, while the number of infused CD34+ cells was 11.84×10^6/kg and 2.33×10^5/kg, respectively. The boy achieved sustained engraftment of both neutrophils and platelets at 16 days and 24 days, respectively, with complete haplo-donor chimerism of confirmed at 14 days. He developed grade III acute GVHD (skin, gut and liver) and recovered at 39 days after transplant. Clinical symptoms such as rash, joint pain and hepatosplenomegaly got complete remission, and the mutated genes like NF1, PTPN11 and COL1A1 all disappeared at 30 days. At the time of this report, the boy was alive with negative MRD and good quality of life with a follow-up of 3 months after HCT. Conclusion:To our knowledge, this is the first report that a child both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta was cured by allogeneic hematopoietic stem cell transplantation.Our experience suggests that allogeneic bone marrow transplantation may be a novel safe and effective therapeutic strategy for OI patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4045-4052 ◽  
Author(s):  
FC Zeigler ◽  
F de Sauvage ◽  
HR Widmer ◽  
GA Keller ◽  
C Donahue ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Progenitor Cell ◽  
Fetal Liver ◽  
Cell Suspension Cultures ◽  
Hematopoietic Stem ◽  
Kit Ligand ◽  
Stem Cell Populations

Recently, the ligand for c-mpl has been identified and cloned. Initial studies of this molecule indicate that it is the platelet regulatory factor, thrombopoietin (TPO). Previous work has indicated that c-mpl is expressed in very immature hematopoietic precursors and thus raised the possibility that TPO may act directly on the hematopoietic stem cell. Therefore, in these studies, we investigate the effects of TPO on hematopoietic stem cell populations isolated from the murine fetal liver and bone marrow. Cocultivation of stem cells with fetal liver stroma give rise to multilineage expansion of the stem cells but with little or no megakaryocytopoiesis. Addition of TPO to these cocultures gives significant megakaryocyte production. This production is enhanced in combination with Kit ligand or interleukin-3. The addition of TPO to stem cell suspension cultures produces a dynamic thrombopoietic system in which stem cells undergo differentiation to produce megakaryocytes and proplatelets. These experiments show that the megakaryocytopoietic and thrombopoietic activities of TPO are initiated at the level of an early progenitor cell or upon the hematopoietic stem cell.

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