Zhu Yuan Xiao, Braggio, Esteban, Shi Chang-Xin, Bruins Laura A, Schmidt Jessica E, Van Wier Scott, Chang Xiu-Bao, Bjorklund Chad C, Fonseca Rafael, Bergsagel P Leif, Orlowski Robert Z, Stewart A Keith "Blood 2011-Nov"
The exact molecular mechanism of motion and targets by means of which thalidomide and associated immunomodulatory medications (IMiDs) exert their antitumor results stays unclear.
We investigated the role of cereblon (CRBN), a primary teratogenic goal of thalidomide, within the antimyeloma activity of IMiDs. CRBN depletion is at first cytotoxic to human myeloma cells, but surviving cells with steady CRBN depletion turn into highly resistant to both lenalidomide and pomalidomide, although not for the unrelated medicines bortezomib, dexamethasone, and melphalan.
Acquired deletion of CRBN was discovered to become the primary genetic occasion differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were drastically suppressed within the presence of CRBN depletion, more demonstrating that CRBN is necessary for lenalidomide activity.
Downstream targets of CRBN contain interferon regulatory element 4 (IRF4) formerly reported to also be a target of lenalidomide. Individuals uncovered to, and putatively resistant to, lenalidomide had reduced CRBN ranges in paired samples before and after treatment.
In summary, CRBN is definitely an crucial requirement for IMiD exercise and a possible biomarker for your medical assessment of antimyeloma efficacy.
2011年11月28日星期一
2011年11月20日星期日
Therapeutic ways in MPN-associated myelofibrosis
Barosi G, Rosti V , Vannucchi AM "EXPERT Viewpoint ON PHARMACOTHERAPY JUL 2011"
Introduction:
Myeloproliferative neoplasm (MPN)-associated myelofibrosis could be the most disabling from the classical Philadelphia-negative MPNs. The discovery that a gain-of-function mutation of JAK2 (JAK2V617F) is existing in far more than 60% of individuals with MPN-associated myelofibrosis has supplied a brand new goal for revolutionary treatment strategies.
Background:
Identification from the JAK2V617F mutation in 2005 boosted simple and clinical research in main myelofibrosis (PMF) along with other Philadelphia-negative persistent myeloproliferative neoplasms. We herein review the recent contributions towards the knowing and conduite of PMF.
In addition to the JAK2V617F mutation, various genetic markers have recently been found in PMF, one of the most appropriate ones being the mutations inside the thrombopoietin (MPL), TET2, and EZH2 genes. In the clinical perspective, interest has recently been compensated to thrombosis as being a relevant complication of PMF and new prognostic designs for this disease happen to be created and refined. With regards to therapy, decreased intensity conditioning regimens have permitted the likelihood of carrying out allogeneic stem cell transplantation in older PMF patients, whereas the first medical trials with JAK2 inhibitors have revealed their efficacy in splenomegaly and constitutional symptoms.
Areas covered:
This evaluation discusses the indications and limitations of typical therapies employed for the remedy of MPN-associated myelofibrosis ahead of reviewing the details offered for new therapies, such as the immunomodulatory and demethylating agents, histone deacethylase, mammalian target of rapamycin (mTOR) and JAK2-inhibitors. The Medline and ASH databases had been searched for medical trials around the health-related therapy of MPN-associated myelofibrosis from early 2000 to December 2010.
Expert opinion:
Three classes of medications have proved to own substantial activity in MPN-associated myelofibrosis. Up to a 40% reaction rate on anemia continues to be documented with the immunomodulator, pomalidomide. The m-TOR inhibitor RAD-001 and different JAK2 inhibitors have documented a profound effect on splenomegaly and constitutional signs and symptoms, with some also having exercise on anemia. These new medications will give medical professionals a lot more possibilities to tailor therapeutic selection in this challenging disease.
Introduction:
Myeloproliferative neoplasm (MPN)-associated myelofibrosis could be the most disabling from the classical Philadelphia-negative MPNs. The discovery that a gain-of-function mutation of JAK2 (JAK2V617F) is existing in far more than 60% of individuals with MPN-associated myelofibrosis has supplied a brand new goal for revolutionary treatment strategies.
Background:
Identification from the JAK2V617F mutation in 2005 boosted simple and clinical research in main myelofibrosis (PMF) along with other Philadelphia-negative persistent myeloproliferative neoplasms. We herein review the recent contributions towards the knowing and conduite of PMF.
In addition to the JAK2V617F mutation, various genetic markers have recently been found in PMF, one of the most appropriate ones being the mutations inside the thrombopoietin (MPL), TET2, and EZH2 genes. In the clinical perspective, interest has recently been compensated to thrombosis as being a relevant complication of PMF and new prognostic designs for this disease happen to be created and refined. With regards to therapy, decreased intensity conditioning regimens have permitted the likelihood of carrying out allogeneic stem cell transplantation in older PMF patients, whereas the first medical trials with JAK2 inhibitors have revealed their efficacy in splenomegaly and constitutional symptoms.
Areas covered:
This evaluation discusses the indications and limitations of typical therapies employed for the remedy of MPN-associated myelofibrosis ahead of reviewing the details offered for new therapies, such as the immunomodulatory and demethylating agents, histone deacethylase, mammalian target of rapamycin (mTOR) and JAK2-inhibitors. The Medline and ASH databases had been searched for medical trials around the health-related therapy of MPN-associated myelofibrosis from early 2000 to December 2010.
Expert opinion:
Three classes of medications have proved to own substantial activity in MPN-associated myelofibrosis. Up to a 40% reaction rate on anemia continues to be documented with the immunomodulator, pomalidomide. The m-TOR inhibitor RAD-001 and different JAK2 inhibitors have documented a profound effect on splenomegaly and constitutional signs and symptoms, with some also having exercise on anemia. These new medications will give medical professionals a lot more possibilities to tailor therapeutic selection in this challenging disease.
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