JAK2 46/1 haplotype proposed mechanisms in MPN risk and progression. The JAK2 46/1 haplotype increases the inherited risk of developing MPNs through 2 proposed mechanisms: (1) it predisposes carriers to the acquisition of JAK2 mutations, and (2) its genetic background provides a selective advantage for clonal outgrowth. In this context, MPN-derived stem cells with high PD-L1 expression may establish an immunosuppressive microenvironment in the bone marrow, promoting disease progression. These mechanistic insights may inform the development of diagnostic and therapeutic strategies aimed at preventing MPN progression, including blocking immune escape mechanisms (eg, PD-L1 inhibition, ADAR1 inhibition) alongside targeting JAK/STAT signaling (eg, JAK2 inhibition, ADAR1 inhibition).

JAK2 46/1 haplotype proposed mechanisms in MPN risk and progression. The JAK2 46/1 haplotype increases the inherited risk of developing MPNs through 2 proposed mechanisms: (1) it predisposes carriers to the acquisition of JAK2 mutations, and (2) its genetic background provides a selective advantage for clonal outgrowth. In this context, MPN-derived stem cells with high PD-L1 expression may establish an immunosuppressive microenvironment in the bone marrow, promoting disease progression. These mechanistic insights may inform the development of diagnostic and therapeutic strategies aimed at preventing MPN progression, including blocking immune escape mechanisms (eg, PD-L1 inhibition, ADAR1 inhibition) alongside targeting JAK/STAT signaling (eg, JAK2 inhibition, ADAR1 inhibition).

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