Browsing by Subject "Leukemia, Myelomonocytic, Juvenile"

Now showing 1 - 3 of 3
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    Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia
    (Ferrata Storti Foundation, 2015-01) Niemeyer, Charlotte M.; Loh, Mignon L.; Cseh, Annamaria; Cooper, Todd; Dvorak, Christopher C.; Chan, Rebecca; Xicoy, Blanca; Germing, Ulrich; Kojima, Seiji; Manabe, Atsushi; Dworzak, Michael; De Moerloose, Barbara; Starý, Jan; Smith, Owen P.; Masetti, Riccardo; Catala, Albert; Bergstraesser, Eva; Ussowicz, Marek; Fabri, Oskana; Baruchel, André; Cavé, Hélène; Zwaan, Michel; Locatelli, Franco; Hasle, Henrik; van den Heuvel-Eibrink, Marry M.; Flotho, Christian; Yoshimi, Ayami; Department of Pediatrics, IU School of Medicine
    Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.
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    Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment
    (SpringerNature, 2016-11-10) Dong, Lei; Yu, Wen-Mei; Zheng, Hong; Loh, Mignon L.; Bunting, Silvia T.; Pauly, Melinda; Huang, Gang; Zhou, Muxiang; Broxmeyer, Hal E.; Scadden, David T.; Qu, Kui; Department of Microbiology & Immunology, IU School of Medicine
    Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias.
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    PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML
    (American Society of Hematology, 2014-05-01) Goodwin, Charles B.; Li, Xing Jun; Mali, Raghuveer S.; Chan, Gordon; Kang, Michelle; Liu, Ziyue; Vanhaesebroeck, Bart; Neel, Benjamin G.; Loh, Mignon L.; Lannutti, Brian J.; Kapur, Reuben; Chan, Rebecca J.; Department of Pediatrics, IU School of Medicine
    Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, the PI3K-Akt signaling pathway is also dysregulated in this disease. Using genetic models, we demonstrate that inactivation of phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110δ, but not PI3K p110α, corrects gain-of-function (GOF) Shp2-induced granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110δ-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK) inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110δ-specific inhibitor, idelalisib, also demonstrates activity against primary leukemia cells from individuals with JMML. These findings suggest that selective inhibition of the PI3K catalytic subunit p110δ could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110δ.