Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal

Frida Holm, Eva Hellqvist, Cayla N. Mason, Shawn A. Ali, Nathaniel Delos-Santos, Christian L. Barrett, Hye Jung Chun, Mark D. Minden, Richard A. Moore, Marco A. Marra, Valeria Runza, Kelly A. Frazer, Anil Sadarangani, Catriona H.M. Jamieson

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Formative research suggests that a human embryonic stem cellspecific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8-10, and BC LSC proliferation. Although isoform-specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region - ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche-dependent manner. In summary, MBNL3 down-regulation-related reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination.

Original languageEnglish
Pages (from-to)15444-15449
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number50
DOIs
StatePublished - 15 Dec 2015
Externally publishedYes

Keywords

  • Adhesion molecules
  • CD44v3
  • MBNL3
  • RNA splicing
  • Self-renewal

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