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Inflammatory bone marrow signaling in pediatric acute myeloid leukemia distinguishes patients with poor outcomes

Author

Listed:
  • Hamid Bolouri

    (Benaroya Research Institute)

  • Rhonda E. Ries

    (Fred Hutchinson Cancer Research Center)

  • Alice E. Wiedeman

    (Benaroya Research Institute)

  • Tiffany Hylkema

    (Fred Hutchinson Cancer Research Center)

  • Sheila Scheiding

    (Benaroya Research Institute)

  • Vivian H. Gersuk

    (Benaroya Research Institute)

  • Kimberly O’Brien

    (Benaroya Research Institute)

  • Quynh-Anh Nguyen

    (Benaroya Research Institute)

  • Jenny L. Smith

    (Fred Hutchinson Cancer Research Center
    Seattle Children’s Research Institute)

  • S. Alice Long

    (Benaroya Research Institute)

  • Soheil Meshinchi

    (Fred Hutchinson Cancer Research Center)

Abstract

High levels of the inflammatory cytokine IL-6 in the bone marrow are associated with poor outcomes in pediatric acute myeloid leukemia (pAML), but its etiology remains unknown. Using RNA-seq data from pre-treatment bone marrows of 1489 children with pAML, we show that > 20% of patients have concurrent IL-6, IL-1, IFNα/β, and TNFα signaling activity and poorer outcomes. Targeted sequencing of pre-treatment bone marrow samples from affected patients (n = 181) revealed 5 highly recurrent patterns of somatic mutation. Using differential expression analyses of the most common genomic subtypes (~60% of total), we identify high expression of multiple potential drivers of inflammation-related treatment resistance. Regardless of genomic subtype, we show that JAK1/2 inhibition reduces receptor-mediated inflammatory signaling by leukemic cells in-vitro. The large number of high-risk pAML genomic subtypes presents an obstacle to the development of mutation-specific therapies. Our findings suggest that therapies targeting inflammatory signaling may be effective across multiple genomic subtypes of pAML.

Suggested Citation

  • Hamid Bolouri & Rhonda E. Ries & Alice E. Wiedeman & Tiffany Hylkema & Sheila Scheiding & Vivian H. Gersuk & Kimberly O’Brien & Quynh-Anh Nguyen & Jenny L. Smith & S. Alice Long & Soheil Meshinchi, 2022. "Inflammatory bone marrow signaling in pediatric acute myeloid leukemia distinguishes patients with poor outcomes," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34965-4
    DOI: 10.1038/s41467-022-34965-4
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