Leukemia-initiating HSCs in chronic lymphocytic leukemia reveal clonal leukemogenesis and differential drug sensitivity

Chi Ling Chiang, Eileen Y. Hu, Lingqian Chang, Jadwiga Labanowska, Kevan Zapolnik, Xiaokui Mo, Junfeng Shi, Tzyy Jye Doong, Arletta Lozanski, Pearlly S. Yan, Ralf Bundschuh, Logan A. Walker, Daniel Gallego-Perez, Wu Lu, Meixiao Long, Sanggu Kim, Nyla A. Heerema, Gerard Lozanski, Jennifer A. Woyach, John C. ByrdLy James Lee, Natarajan Muthusamy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The existence of “leukemia-initiating cells” (LICs) in chronic lymphocytic leukemia (CLL) remains controversial due to the difficulty in isolating and identifying the tumor-initiating cells. Here, we demonstrate a microchannel electroporation (MEP) microarray that injects RNA-detecting probes into single live cells, allowing the imaging and characterization of heterogeneous LICs by intracellular RNA expression. Using limited-cell FACS sequencing (LC-FACSeq), we can detect and monitor rare live LICs during leukemogenesis and characterize their differential drug sensitivity. Disease-associated mutation accumulation in developing B lymphoid but not myeloid lineage in CLL patient hematopoietic stem cells (CLL-HSCs), and development of independent clonal CLL-like cells in murine patient-derived xenograft models, suggests the existence of CLL LICs. Furthermore, we identify differential protein ubiquitination and unfolding response signatures in GATA2high CLL-HSCs that exhibit increased sensitivity to lenalidomide and resistance to fludarabine compared to GATA2lowCLL-HSCs. These results highlight the existence of therapeutically targetable disease precursors in CLL.

Original languageEnglish
Article number111115
JournalCell Reports
Volume40
Issue number3
DOIs
StatePublished - 19 Jul 2022

Keywords

  • chronic lymphocytic leukemia
  • CP: Cancer
  • fludarabine
  • GATA2
  • IKZF1
  • LC-FACSeq
  • lenalidomide
  • leukemia initiating cells
  • single-cell analysis
  • stem cells

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