Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/- c-/- mice

Krombholz, Christopher Felix; Aumann, Konrad; Kollek, Matthias; Bertele, Daniela; Fluhr, Silvia; Kunze, Mirjam; Niemeyer, Charlotte M.; Flotho, Christian; Erlacher, Miriam

doi:10.3324/haematol.2015.138545

Cited by 20 publications

(21 citation statements)

References 41 publications

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“…On the other hand, circulating T lymphocytes from most patients do not express the disease-initiating mutation (7,37), suggesting that JMML is initiated within a MPP that undergoes a differentiation block during T lymphocyte commitment. Consistent with this hypothesis, case reports suggest that patients with JMML have decreased T cell frequencies in the BM and spleen (38,39). These findings parallel our Flt3Cre + Kras G12D model, which has a paucity of T cells, an atrophied thymus, and abnormal T cell differentiation.…”

Section: Gr1supporting

confidence: 77%

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia

Tarnawsky¹,

Kobayashi²,

Chan

et al. 2017

Journal of Clinical Investigation

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Section: Gr1supporting

confidence: 77%

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia

Tarnawsky¹,

Kobayashi²,

Chan

et al. 2017

Journal of Clinical Investigation

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“…5,7,8 Unlike CMML, for which serially transplantable and genetically accurate PDX models have not been generated previously, a serially transplantable JMML model has recently been described in RAGIL2Rg null mice. 39 Tail vein injection of unfractionated BM (2.2-4. Table 1) and lethality of recipient mice at a median of 43 days ( Figure 3C).…”

Section: Successful Generation Of Jmml Xenografts In Nsgs Micementioning

confidence: 99%

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Yoshimi

Balasis

Vedder

et al. 2017

Blood

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• Genetically accurate xenografts of CMML are achievable with near 100% frequency in NSGS mice.• Robust human engraftment and overt phenotypes of CMML and JMML xenografts here facilitate preclinical therapeutic evaluation in vivo.Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rg null background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34 1 cells (n 5 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n 5 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n 5 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34 1 cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34 1 cells as harboring the disease-initiating compartment in vivo.Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n 5 4 patients, n 5 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders. (Blood. 2017;130(4):397-407)

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“…Therapeutic approaches range from watchful monitoring to allogeneic hematopoietic stem cell transplantation (HSCT) performed in early stages (3). Clinical symptoms result from hematopoietic insufficiency and leukemic infiltration of various organs, such as spleen, liver, skin, lung, and gastrointestinal tract (4). Conventional cytogenetics studies indicate monosomy 7 in up to 25% of JMML patients and other abnormalities in 10% of cases.…”

Section: Introductionmentioning

confidence: 99%

“…The other two subtypes (20-30% of JMML cases) occur in patients with underlying constitutional diseases caused by germline mutations in the RAS pathways (RASopathies): neurofibromatosis type 1 (NF1) and Noonan-like "CBL syndrome, " respectively. Hematological disorders develop due to the acquired loss of heterozygosity of the constitutionally affected NF1 or CBL tumor suppressor genes in the hematopoietic progenitors (4,10,11). In rare cases of JMML that lack the above-mentioned mutations, heterozygous somatic RRAS mutations have been reported as disease drivers (12).…”

Section: Introductionmentioning

confidence: 99%

Single-Center Experience With Epigenetic Treatment for Juvenile Myelomonocytic Leukemia

et al. 2020

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Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/- c-/- mice

Cited by 20 publications

References 41 publications

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia

Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Single-Center Experience With Epigenetic Treatment for Juvenile Myelomonocytic Leukemia

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