Browsing by Subject "Myeloproliferative Disorders"

Now showing 1 - 5 of 5
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    Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder
    (Impact Journals, LLC, 2015-07-30) Chatterjee, Anindya; Ghosh, Joydeep; Kapur, Reuben; Department of Pediatrics, IU School of Medicine
    Although more than 90% systemic mastocytosis (SM) patients express gain of function mutations in the KIT receptor, recent next generation sequencing has revealed the presence of several additional genetic and epigenetic mutations in a subset of these patients, which confer poor prognosis and inferior overall survival. A clear understanding of how genetic and epigenetic mutations cooperate in regulating the tremendous heterogeneity observed in these patients will be essential for designing effective treatment strategies for this complex disease. In this review, we describe the clinical heterogeneity observed in patients with mastocytosis, the nature of relatively novel mutations identified in these patients, therapeutic strategies to target molecules downstream from activating KIT receptor and finally we speculate on potential novel strategies to interfere with the function of not only the oncogenic KIT receptor but also epigenetic mutations seen in these patients.
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    Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner
    (Elsevier, 2014-07-03) Wang, Lin; Zhang, Huajia; Rodriguez, Sonia; Cao, Liyun; Parish, Jonathan; Mumaw, Christen; Zollman, Amy; Kamocka, Gosia; Mu, Jian; Chen, Danny Z.; Srour, Edward F.; Chitteti, Brahmananda R.; HogenEsch, Harm; Tu, Xiaolin; Bellido, Teresita M.; Boswell, Scott; Manshouri, Taghi; Verstovsek, Srdan; Yoder, Mervin C.; Kapur, Reuben; Cardoso, Angelo A.; Carlesso, Nadia; Department of Pediatrics, IU School of Medicine
    The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative-like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor κB (NF-κB) inhibitor κB-Ras1, NF-κB activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ(-/-) mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.
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    Role of intracellular tyrosines in activating KIT induced myeloproliferative disease
    (Nature Publishing Group, 2012-07) Ma, Peilin; Mali, Raghuveer Singh; Martin, Holly; Ramdas, Baskar; Sims, Emily; Kapur, Reuben; Department of Pediatrics, IU School of Medicine
    Gain-of-function mutations in KIT receptor in humans are associated with gastrointestinal stromal tumors (GIST), systemic mastocytosis (SM), and acute myelogenous leukemia (AML). The intracellular signals that contribute to oncogenic KIT induced myeloproliferative disease (MPD) are poorly understood. Here, we show that oncogenic KITD814V induced MPD occurs in the absence of ligand stimulation. The intracellular tyrosine residues are important for KITD814V induced MPD, albeit to varying degrees. Among the seven intracellular tyrosines examined, tyrosine 719 alone plays a unique role in regulating KITD814V induced proliferation and survival in vitro, and MPD in vivo. Importantly, the extent to which AKT, ERK and Stat5 signaling pathways are activated via the seven intracellular tyrosines in KITD814V impacts the latency of MPD and severity of the disease. Our results identify critical signaling molecules involved in regulating KITD814V induced MPD, which might be useful for developing novel therapeutic targets for hematologic malignancies involving this mutation.
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    Shp2 function in hematopoietic stem cell biology and leukemogenesis
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2012-07) Nabinger, Sarah C.; Chan, Rebecca J.; Department of Pediatrics, IU School of Medicine
    PURPOSE OF REVIEW: The protein tyrosine phosphatase Shp2 is encoded by PTPN11 and positively regulates physiologic hematopoiesis. Mutations of PTPN11 cause the congenital disorder Noonan syndrome and pathologically promote human leukemias. Given the high frequency of PTPN11 mutations in human disease, several animal models have been generated to investigate Shp2 in hematopoietic stem cell (HSC) function and leukemic transformation. RECENT FINDINGS: Two independent animal models bearing knockout of Shp2 in hematopoietic tissues clearly demonstrate the necessity of Shp2 in HSC repopulating capacity. Reduced HSC quiescence and increased apoptosis accounts for diminished HSC function in the absence of Shp2. The germline mutation Shp2D61G enhances HSC activity and induces myeloproliferative disease (MPD) in vivo by HSC transformation. The somatic mutation Shp2D61Y produces MPD in vivo but fails to induce acute leukemia, whereas somatic Shp2E76K produces MPD in vivo that transforms into full-blown leukemia. HSCs expressing Shp2D61Y do not generate MPD in recipient animals upon transplantation, whereas Shp2E76K-expressing HSCs yield MPD as well as acute leukemia in recipient animals. The mechanisms underlying the unique functions of Shp2D61Y and Shp2E76K in HSC transformation and leukemogenesis continue to be under investigation. SUMMARY: Further understanding of the physiologic and pathologic role of Shp2 in hematopoiesis and leukemogenesis, respectively, will yield information needed to develop therapeutic strategies targeted to Shp2 in human disease.
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    Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms
    (Springer (Biomed Central Ltd.), 2015) Pandey, Ruchi; Kapur, Reuben; Department of Pediatrics, IU School of Medicine
    Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR-ABL1 fusion + ve (Ph + ve) or -ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosine kinases in the clinic have triggered the search for kinase dependent pathways in other Ph-ve MPNs. In the past few years, identification of mutations in JAK2 associated with a majority of MPNs raised the hopes for similar success with specific targeting of JAK2. However, targeting JAK2 kinase activity has met with limited success. Subsequently, mutations in genes other than JAK2 have been identified. These mutations specifically associate with certain MPNs and can drive cytokine independent growth. Therefore, targeting alternate molecules and pathways may be more successful in management of MPNs. Among other pathways, phosphatidylinositol -3 kinase (PI3K) has emerged as a promising target as different cell surface receptor induced signaling pathways converge on the PI3K signaling axis to regulate cell metabolism, growth, proliferation, and survival. Herein, we will review the clinically relevant inhibitors of the PI3K pathway that have been evaluated or hold promise for the treatment of Ph-ve MPNs.