What question did this study set out to answer?

Determine whether activating mutations in cytokine receptors cause constitutive JAK-STAT signaling in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia.

July 11, 2006PLoS MedicineOpen Access

MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia

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Authors

YPYana PikmanBroad Institute BLBenjamin H. LeeCambridge Scientific (United States)TMThomas MercherInserm

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Implication

Translational study uncovers an activating MPLW515L mutation in JAK2V617F-negative myelofibrosis, indicating an alternative driver of aberrant JAK-STAT pathway signaling.

Key Points

Determine whether activating mutations in cytokine receptors cause constitutive JAK-STAT signaling in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia.
Sequenced exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR in JAK2V617F-negative myelofibrosis patients (n=45) and matched buccal germline DNA.
Expressed MPLW515L in 32D, UT7, and Ba/F3 cells to evaluate cytokine-independent proliferation, downstream phosphorylation, and sensitivity to a small-molecule JAK kinase inhibitor.
Assessed disease pathogenesis in vivo using a murine bone marrow transplantation model expressing wild-type MPL or MPLW515L.
Identified a somatic MPLW515L transmembrane mutation in 9% (4/45) of patients with JAK2V617F-negative myelofibrosis.
MPLW515L expression promoted cytokine-independent growth and constitutive activation of JAK2, STAT3, STAT5, AKT, and ERK, which was successfully reversed by JAK kinase inhibition in vitro.
Mice transplanted with MPLW515L-expressing cells developed fully penetrant disease with thrombocytosis (platelets 1.9–4.0 x 10^12/L), splenomegaly via extramedullary hematopoiesis, and reticulin fibrosis.

Cite This Study

Pikman et al. (2006) studied this question.

synapsesocial.com/papers/6a11da8b3e1890633cb4d56f https://doi.org/10.1371/journal.pmed.0030270

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Implication

Translational study uncovers an activating MPLW515L mutation in JAK2V617F-negative myelofibrosis, indicating an alternative driver of aberrant JAK-STAT pathway signaling.

MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia

Discussion

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Implication

Key Points

Cite This Study

MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia

Discussion

Member takes

Implication

Key Points

Cite This Study

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