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Immature CML cells Implement a BMP Autocrine Loop to Escape TKI Treatment

Elodie Grockowiak, Bastien Laperrousaz, Sandrine Jeanpierre, Thibault Voeltzel, Boris Guyot, Stéphanie Gobert, Franck E. Nicolini and Véronique Maguer-Satta

Key points

  • TKI resistant CML patients display persistent BMP pathway alterations in leukemic immature cells and their niche.

  • A subpopulation of TKI-resistant leukemic stem cells survives through binding of BMP4 to BMPR1b that preserves TWIST-1 expressing cells.

Abstract

The BCR-ABL specific Tyrosine Kinase Inhibitors (TKI) changed the outcome of Chronic Myeloid Leukemia (CML), turning a life-threatening disease into a chronic illness. However, TKI are not yet curative, since most patients retain leukemic stem cells (LSC) and their progenitors in bone marrow and relapse following treatment cessation. At diagnosis, deregulations of the Bone Morphogenetic Proteins (BMP) pathway are involved in LSC and progenitors expansion. Here, we report that BMP pathway alterations persist in TKI-resistant patients. As compared to patients in Complete Cytogenetic Remission (CCyR), TKI-resistant LSC and progenitors display high levels of BMPR1b expression and alterations of its cellular localization. In vitro treatment of immature chronic phase (CP) CML cells with TKI alone, or in combination with IFN-α results in the preferential survival of BMPR1b+ cells. We demonstrated persistent and increasing BMP4 production by patients' mesenchymal cells with resistance. Patient follow-up revealed an increase of BMPR1b expression and also in BMP4 expression in LSC from TKI-resistant patients as compared to diagnosis, while remaining unchanged in sensitive patients. Both leukemic and non-leukemic cells exhibit higher BMP4 levels in the bone marrow of TKI-resistant patients. Exposure to BMP2/BMP4 does not alter BCR-ABL transcript expression, but is accompanied by the overexpression of TWIST-1, a transcription factor highly expressed in resistant LSC. By modulating BMP4 or BMPR1b expression, we show that these elements are involved in TKI-resistance. To summarize, we revealed that persistence of BMP alterations and existence of an autocrine loop promote CML primitive cells TKI-resistance.

  • Submitted August 9, 2017.
  • Accepted November 3, 2017.