While inhibitors directed against BCR ABL1 fusion gene aberrant JAK2 inhibitors directed against a gene whiHP is in normal cells and play an r Important in the development of h Hematopoietic ESE normal. This means that side effects of JAK2 inhibitors at doses k Can l embroidered myeloproliferative Ph Induced phenotype, often induce rank 4 M Rz h Hematological toxicity t, As observed Bergenin in clinical studies. Limits the clinical efficacy of JAK2 inhibitors Several studies describe the occurrence of reversible grade 3 or 4 hours Hematological toxicity t between 3-35%, dependent Ngig specificity of the t of the inhibitor. Other h INDICATIVE side effects are symptoms My stomach is probably related to the inhibition of other kinases. The incidence of nausea, vomiting and diarrhea varies between 5-70%, dependent Ngig of the connection. So far it is known that JAK2 is a member of a family of tyrosine kinases in the cytoplasm of h Hematopoietic cells Ethical.
Recently it was shown that JAK2 is also present in the nuclei of h Hematopoietic cells Ethical indirectly where it activates the expression of oncogenes such as LMO2. It is not yet known, there JAK2 inhibitors have an r In the inhibition of the function of nuclear JAK2. In coming years, the increasing experience with clinical and biological 2-Methoxyestradiol JAK2 inhibitors is small Ren their r It. Although imatinib in CML can not be directly compared with the inhibition of JAK2 in MPN, it can be used as a model for clinical experience with TK inhibitors. Therefore, k We can on what is happening with the use of speculating JAK2 inhibitors in clinical practice. One k Nnte Resistance to JAK2 inhibitors by acquiring mutations in the ATP binding pocket of the TK Dom ne expect of JAK2 and / or amplification of JAK2.
We can k Expect that JAK2 inhibitors are effective in relieving the symptoms My clinical patients with MPN, when used as monotherapy, but ineffective to cure the disease as it occurred with imatinib. Clinical studies with inhibitors of JAK2 withmyelofibrosis patients have demonstrated the effectiveness of these drugs in order to reduce the symptoms Splenomegaly my clinics and improve the quality of t of life. However, in these studies was the strain of JAK2 slightly reduced, indicating that JAK2 inhibitors are responsible for the blocking of the cytokine-way for the symptoms effective My effective clinical patients with MPN, but not sufficient, the key molecular mechanism that is originally from the disease block.
Recently showed Mullally et al., Using blow of a JAK2V617F MPN mouse model there JAK2 inhibitors embroidered k can L berm Cent proliferation of h Hematopoietic Preferences Shore cells are Ethical in MPN engagement, but not to remove the population of cells, of which the clone initiator formed. This cell population was identified as h Hematopoietic Preferences Shore cells noncommitted Ethical JAK2V617F, Lin Sca c-kit. JAK2 inhibitors in combination with drugs that target the LSK Bev k POPULATION noncommitted positive NPP can be used to heal. Given the fact that JAK2 inhibitors inducemyelosuppression not heal k MPN can seem combinations with other compounds, the therapeutic synergy of JAK2 inhibitors may be mandatory.