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

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