10 Questions
What is the percentage of JAK2V617F-negative myelofibrosis (MF) patients that have a somatic activating mutation in the transmembrane domain of MPL?
9%
What is the name of the pathway that is constitutively activated in patients with polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia?
JAK-STAT signal transduction pathway
What is the effect of expressing MPLW515L in cells such as 32D, UT7, or Ba/F3?
It confers cytokine-independent growth and thrombopoietin hypersensitivity, and results in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK.
What is the therapeutic potential of inhibiting JAK2V617F in patients with polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia?
It may be of therapeutic benefit.
What is the effect of a small molecule JAK kinase inhibitor on MPLW515L-mediated proliferation and JAK-STAT signaling?
It inhibits it.
What is the proportion of patients with essential thrombocytosis (ET) or myelofibrosis (MF) that are JAK2V617F-negative?
A significant proportion
What is the name of the receptor that was found to have a somatic activating mutation in the transmembrane domain in JAK2V617F-negative MF patients?
MPL (thrombopoietin receptor)
What is the amino acid substitution in the MPL receptor that leads to its activation?
W515L
What is the purpose of comparing DNA sequence analysis of cytokine receptors with germline DNA derived from buccal swabs?
To identify somatic mutations.
What is the significance of the JAK-STAT pathway in patients with polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia?
It is an important pathogenetic event.
Study Notes
JAK2V617F and Myeloproliferative Disorders
- JAK2V617F allele is identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF)
- Constitutive activation of the JAK-STAT signal transduction pathway is a key pathogenetic event in these patients
JAK2V617F-Negative Patients
- A significant proportion of patients with ET or MF are JAK2V617F-negative
- Alternative mechanisms of JAK-STAT pathway activation may be present in these patients
Activating Mutations in Cytokine Receptors
- Activating mutations in certain hematopoietic-specific cytokine receptors, such as EPOR, MPL, or GCSFR, may activate the JAK-STAT pathway
- A somatic activating mutation in the transmembrane domain of MPL (W515L) was identified in 9% of JAK2V617F-negative MF patients
Characteristics of MPLW515L
- Expression of MPLW515L in cells confers cytokine-independent growth and thrombopoietin hypersensitivity
- MPLW515L results in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK
- A small molecule JAK kinase inhibitor inhibits MPLW515L-mediated proliferation and JAK-STAT signaling in vitro
Murine Bone Marrow Transplant Assay
- Expression of MPLW515L in a murine bone marrow transplant assay results in a fully penetrant myeloproliferative disorder
- Features of this disorder include:
- Marked thrombocytosis (Plt count 1.9–4.0 × 10^12/L)
- Marked splenomegaly due to extramedullary hematopoiesis
- Increased reticulin fibrosis
Conclusion
- Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF
- Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD
This quiz covers the JAK2V617F allele and its role in polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia. It also explores the constitutive activation of the JAK-STAT signal transduction pathway and potential therapeutic benefits of JAK2V617F inhibition.
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