EXEL-8232, a small-molecule JAK2 inhibitor, effectively treats thrombocytosis and extramedullary hematopoiesis in a murine model of myeloproliferative neoplasm induced by MPLW515L

Wernig, Gerlinde; Kharas, Michael G.; Mullally, Ann; Leeman, Dena S.; Okabe, Rachel; George, Tracy I.; Clary, Douglas O.; Gilliland, D. Gary

doi:10.1038/leu.2011.261

Cited by 16 publications

(16 citation statements)

References 20 publications

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“…As some small-molecule JAK2 inhibitors have shown efficacy in murine models of MPL W515L [20, 21], identification and characterisation of further cases of non-familial, MPL S505N-mutated MPN is required as these patients may benefit therapeutically from such strategies and also to determine features that may influence the risk of both thrombotic events and fibrotic disease progression.…”

Section: Discussionmentioning

confidence: 99%

Nonfamilial,MPLS505N-Mutated Essential Thrombocythaemia

Morrell

Langabeer

Smyth

et al. 2013

Case Reports in Hematology

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Mutations of MPL are present in a significant proportion of patients with the myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF), and essential thrombocythaemia (ET). The most frequent of these mutations, W515L and W515K, occur in exon 10 of MPL, which encodes the receptor for thrombopoietin. Another exon 10 mutation, MPL S505N, has been shown to be a founder mutation in several pedigrees with familial thrombocythaemia where it is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Rare cases of sporadic, nonfamilial, MPL S505N MPN have been documented, but the presenting laboratory and clinical features have not been described in detail. The diagnosis and clinical course of a case of MPL S505N-positive MPN are presented with diagnostic features and treatment response resembling typical ET but with evidence of increasing bone marrow fibrosis. Further MPN cases possessing this genotype require reporting in order to ascertain whether any particular morphological or clinical features, if present, determine clinical course and aid the refinement of therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Nonfamilial,MPLS505N-Mutated Essential Thrombocythaemia

Morrell

Langabeer

Smyth

et al. 2013

Case Reports in Hematology

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“…In a retroviral BMT assay, MPLW515L induced a MPN in mice, characterized by leukocytosis, thrombocytosis, splenomegaly and reticulin fibrosis 38 . This model has subsequently been used to provide preclinical evidence in support of the use of JAK2 kinase inhibitors in MPN patients who carry the MPLW515L mutation 40,41 .…”

Section: B Mpn Murine Modelsmentioning

confidence: 99%

Myeloproliferative Neoplasm Animal Models

Mullally

Lane

Brumme

et al. 2012

Hematology/Oncology Clinics of North America

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Synopsis Myeloproliferative neoplasm (MPN) animal models accurately re-capitulate human disease in mice and have been an important tool for the study of MPN biology and therapy. Transplantation of BCR-ABL transduced bone marrow cells into irradiated syngeneic mice established the field of MPN animal modeling and the retroviral bone marrow transplantation (BMT) assay has been used extensively since. Genetically engineered MPN animal models have enabled detailed characterization of the effects of specific MPN associated genetic abnormalities on the hematopoietic stem and progenitor cell (HSPC) compartment and xenograft models have allowed the study of primary human MPN-propagating cells in vivo. All models have facilitated the pre-clinical development of MPN therapies. JAK2V617F, the most common molecular abnormality in BCR-ABL negative MPN, has been extensively studied using retroviral, transgenic, knock-in and xenograft models. MPN animal models have also been used to investigate additional genetic lesions found in human MPN and to evaluate the bone marrow microenvironment in these diseases. Finally, several genetic lesions, although not common, somatically mutated drivers of MPN in humans induce a MPN phenotype in mice. Future uses for MPN animal models will include modeling compound genetic lesions in MPN and studying myelofibrotic transformation.

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“…52 EXEL-8232, a structurally similar compound to XL-019, was evaluated in a mouse MPLW515L transplant ET model where it led to resolution of thrombocytosis, leukocytosis, hepatosplenic EMH, and bone marrow fibrosis, without causing anemia. 57 …”

Section: Targeting Jak-stat: How Robust Is the Scientific Rationale?mentioning

confidence: 99%