Identification of Chemotherapy-Induced Leukemic-Regenerating Cells Reveals a Transient Vulnerability of Human AML Recurrence

Cancer Cell. 2018 Sep 10;34(3):483-498.e5. doi: 10.1016/j.ccell.2018.08.007.

Abstract

Despite successful remission induction, recurrence of acute myeloid leukemia (AML) remains a clinical obstacle thought to be caused by the retention of dormant leukemic stem cells (LSCs). Using chemotherapy-treated AML xenografts and patient samples, we have modeled patient remission and relapse kinetics to reveal that LSCs are effectively depleted via cell-cycle recruitment, leaving the origins of relapse unclear. Post-chemotherapy, in vivo characterization at the onset of disease relapse revealed a unique molecular state of leukemic-regenerating cells (LRCs) responsible for disease re-growth. LRCs are transient, can only be detected in vivo, and are molecularly distinct from therapy-naive LSCs. We demonstrate that LRC features can be used as markers of relapse and are therapeutically targetable to prevent disease recurrence.

Keywords: AML; LRCs; LSCs; chemotherapy; leukemia; leukemia stem cells; leukemic microenvironment; leukemic-regenerating cells; relapse; xenograft.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Cycle / drug effects
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Myeloid Progenitor Cells / drug effects*
  • Myeloid Progenitor Cells / pathology
  • Neoplasm Recurrence, Local / diagnosis
  • Neoplasm Recurrence, Local / prevention & control*
  • Primary Cell Culture
  • Prognosis
  • Regeneration / drug effects*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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