title: Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms.
abstract: 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.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. pandeyru@iupui.edu.|Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. pandeyru@iupui.edu.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Pandey
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. rkapur@iupui.edu.|Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. rkapur@iupui.edu.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. rkapur@iupui.edu.|Department of Molecular Biology and Biochemistry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. rkapur@iupui.edu.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D010677:Philadelphia Chromosome; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D058539:Phosphatidylinositol 3-Kinase