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    Home > Active Ingredient News > Blood System > Leukemia: The dual targeting of JAK2 and ERK interferes with myeloproliferative tumor cloning and improves the therapeutic effect

    Leukemia: The dual targeting of JAK2 and ERK interferes with myeloproliferative tumor cloning and improves the therapeutic effect

    • Last Update: 2021-12-26
    • Source: Internet
    • Author: User
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    Myeloproliferative neoplasm (MPN) is a clonal hematopoietic stem cell disease characterized by excessive export of mature myeloid cells and an inherent risk of leukemia transformation
    .


    MPN shows that JAK2 signaling is dysregulated, and JAK2 inhibitors can provide clinical benefits, but the compensatory activation of MAPK pathway signaling can hinder its efficacy


    Myeloproliferative neoplasm (MPN) is a clonal hematopoietic stem cell disease characterized by excessive export of mature myeloid cells and an inherent risk of leukemia transformation


    Here, a research team hypothesized that the dual targeting of JAK2 and ERK1/2 can enhance clonal control and therapeutic effects


    Figure 1: Genetic targeting of ERK1/2 alleviates the MPN phenotype and damages the Jak2V617F clone


     Competitive transplantation of Jak2 V617F with wild-type bone marrow (BM) showed that ERK1/2 deficiencies in hematopoiesis alleviated MPN characteristics and reduced V617F clones in the blood and hematopoietic progenitor cell compartments of Jak2 .
    ERK1/2 ablation combined with JAK2 inhibition inhibits the MAPK transcription program, normalizes cell proliferation and promotes clonal control, indicating that dual JAK2/ERK1/2 targeting is an enhanced correction method .

     Competitive transplantation of Jak2 V617F with wild-type bone marrow (BM) showed that ERK1/2 deficiencies in hematopoiesis alleviated MPN characteristics and reduced V617F clones in the blood and hematopoietic progenitor cell compartments of Jak2 .


    ERK1/2 ablation combined with JAK2 inhibition inhibits the MAPK transcription program, normalizes cell proliferation and promotes clonal control, indicating that dual JAK2/ERK1/2 targeting is an enhanced correction method .

    Figure 2: ERK1/2 gene targeting enhances thecorrective effect of Ruxotinib on JAK2 inhibition in Jak2 V617F mice
    .

    Figure 2: ERK1/2 gene targeting enhances thecorrective effect of Ruxotinib on JAK2 inhibition in Jak2 V617F mice
    .


    Jak2

    Figure 3: ERK1/2 inhibition increases thesensitivity of Jak2 V617F cells to JAK2 inhibition
    .

    Figure 3: ERK1/2 inhibition increases thesensitivity of Jak2 V617F cells to JAK2 inhibition
    .


    Figure 3: ERK1/2 inhibition increases thesensitivity of Jak2 V617F cells to JAK2 inhibition


    Combined pharmacological JAK2/ERK1/2 inhibition with Ruxotinib and ERK inhibitors can reducethe proliferation of Jak2 V617F cells and correctpolycythemia and splenomegaly in Jak2 V617F MPN mice
    .


    Long-term treatment can induce a decrease in clones


    Combined pharmacological JAK2/ERK1/2 inhibition with Ruxotinib and ERK inhibitors can reducethe proliferation of Jak2 V617F cells and correctpolycythemia and splenomegaly in Jak2 V617F MPN mice


    Figure 4: The dual inhibition of JAK2 and ERK1/2 by ruxolitinib/LTT462 enhances thetherapeutic effect of the Jak2 V617F MPN preclinical model


    Figure 5: The dual inhibition of JAK2 and ERK1/2 by ruxolitinib/LTT462 enhances thetherapeutic effect of the MPL W515L MPN preclinical model
    .

    Figure 5: The dual inhibition of JAK2 and ERK1/2 by ruxolitinib/LTT462 enhances thetherapeutic effect of the MPL W515L MPN preclinical model
    .


    Figure 5: The dual inhibition of JAK2 and ERK1/2 by ruxolitinib/LTT462 enhances thetherapeutic effect of the MPL W515L MPN preclinical model


    Figure 6: JAK2 and ERK1/2 dual inhibition enhances the inhibitionof bone marrow colony formation and ERK1/2 target activation in primary JAK2 V617F patient cells
    .

    Figure 6: JAK2 and ERK1/2 dual inhibition enhances the inhibitionof bone marrow colony formation and ERK1/2 target activation in primary JAK2 V617F patient cells
    .


    Figure 6: JAK2 and ERK1/2 dual inhibition enhances the inhibitionof bone marrow colony formation and ERK1/2 target activation in primary JAK2 V617F patient cells
    .
    JAK2

    In summary, their data shows that the dual targeting of JAK2 and ERK1/2 effectively resolves ERK1/2 kinase as the second node of oncogenic signaling, which ensures the inhibition of MPN
    .
    It is also shown here that the dual targeting of JAK2 and ERK1/2 leads to enhanced therapeutic performance in several MPN environments, so it should be pursued as a mechanism-based treatment method for MPN patients
    .

     

    Original source:

    Brkic, S.
    , Stivala, S.
    , Santopolo, A.
      et al.
     Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy.
      Leukemia  35,  2875–2884 (2021).
    https://doi.
    org/10.
    1038/s41375-021-01391-2.

    et al.
    Leukemia 35,  leave a message here
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