Parallel Evolution of Leukemic Clones in Myeloproliferative Neoplasms.

Area of Science:

• Hematology
• Cancer Biology
• Molecular Oncology

Background:

• Myeloproliferative neoplasms (MPNs) are often driven by the JAK2 V617F mutation.
• Progression to secondary acute myeloid leukemia (sAML) significantly worsens prognosis.
• Alternative transformation mechanisms beyond JAK2 mutation cooperation are suggested by JAK2-negative sAML cases.

Purpose of the Study:

• Investigate alternative mechanisms of leukemic transformation in MPN.
• Identify factors driving the emergence and selection of leukemia-initiating clones.
• Explore therapeutic strategies to prevent leukemic evolution in MPN.

Main Methods:

• Utilized patient samples and in vivo modeling.
• Performed convergent profiling of mouse and human models.
• Assessed the impact of cytokine inhibition on leukemia-initiating clones.

Main Results:

• Identified TET2-mutant clones emerging independently of JAK2-mutant cells.
• Demonstrated positive selection of TET2-mutant clones in the MPN inflammatory environment.
• Showcased IL-12 and TNFα as key extrinsic selective pressures.
• Confirmed that inhibiting these cytokines mitigates the advantage of TET2-mutant cells.

Conclusions:

• Leukemic evolution in MPN can occur via parallel acute myeloid leukemia (pAML) clones independent of the primary disease.
• IL-12 and TNFα signaling represent potential therapeutic targets to prevent leukemic transformation.
• Established a new paradigm for clonal evolution in blood neoplasms.