HIF-1α of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target

Clin Cancer Res. 2014 Feb 15;20(4):847-58. doi: 10.1158/1078-0432.CCR-13-1950. Epub 2013 Dec 2.


Purpose: To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.

Experimental design: HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.

Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival.

Conclusions: The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Bone Marrow Cells / metabolism*
  • Boronic Acids / pharmacology
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Drug Resistance, Neoplasm
  • Endothelial Cells / metabolism*
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hydroxamic Acids / pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Indoles / pharmacology
  • Kaplan-Meier Estimate
  • Lenalidomide
  • Male
  • Middle Aged
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / mortality
  • Multiple Myeloma / pathology
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasm Recurrence, Local / prevention & control
  • Neovascularization, Pathologic / metabolism
  • Panobinostat
  • Proteome / genetics
  • Proteome / metabolism
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use
  • Reactive Oxygen Species / metabolism
  • Thalidomide / analogs & derivatives
  • Thalidomide / pharmacology
  • Thalidomide / therapeutic use
  • Transcription, Genetic


  • Antineoplastic Agents
  • Boronic Acids
  • HIF1A protein, human
  • Hydroxamic Acids
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indoles
  • Proteome
  • Pyrazines
  • Reactive Oxygen Species
  • Thalidomide
  • Bortezomib
  • Panobinostat
  • Lenalidomide