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Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras.

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Summary
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Targeting the phosphoinositide-3'-OH kinase (PI3K)/Akt pathway shows promise for treating chronic and juvenile myelomonocytic leukemias (CMML and JMML). Inhibiting Akt, but not PI3K, effectively improved hematologic responses in mouse models of these challenging myeloid cancers.

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Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are rare myeloid neoplasms with poor prognoses.
  • Aberrant Ras pathway signaling due to mutations in NRAS, KRAS, PTPN11, CBL, and NF1 is a hallmark of CMML and JMML.
  • Current treatments for CMML and JMML are largely ineffective, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting Ras-regulated effector pathways, specifically the phosphoinositide-3'-OH kinase (PI3K)/Akt cascade, in CMML and JMML.
  • To evaluate the efficacy of PI3K and Akt inhibitors in preclinical mouse models of these myeloid malignancies.

Main Methods:

  • Utilized Mx1-Cre, Kras(D12) and Mx1-Cre, Nf1(flox/)(-) mouse models that accurately recapitulate key features of CMML and JMML.
  • Administered GDC-0941 (a PI3K inhibitor) and MK-2206 (an Akt inhibitor) to evaluate their impact on hematologic parameters and survival.
  • Assessed the effects of these inhibitors on both PI3K/Akt and Raf/MEK/ERK signaling pathways in primary hematopoietic cells.

Main Results:

  • Treatment with GDC-0941 reduced leukocytosis, anemia, and splenomegaly, extending survival in Kras(D12) mice.
  • GDC-0941 treatment affected both PI3K/Akt and Raf/MEK/ERK pathways, suggesting potential off-target effects or complex pathway interactions.
  • Administration of the Akt inhibitor MK-2206, without impacting Raf/MEK/ERK signaling, induced significant hematologic improvements in Kras and Nf1 mouse models of myeloproliferative neoplasms.

Conclusions:

  • The PI3K/Akt pathway is a critical driver in CMML and JMML pathogenesis.
  • Targeting the Akt pathway specifically, independent of Raf/MEK/ERK signaling, offers a promising therapeutic avenue for CMML and JMML.
  • These findings support the clinical investigation of PI3K/Akt pathway inhibitors for patients diagnosed with CMML and JMML.