Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells

Area of Science:

• Hematology
• Oncology
• Stem Cell Biology

Background:

• Multiple myeloma (MM) is a plasma cell malignancy often leading to impaired blood cell production (hematopoiesis).
• Hematopoietic stem and progenitor cells (HSPCs) are crucial for blood cell formation and are found diminished in MM patients' bone marrow (BM).

Purpose of the Study:

• To investigate the impact of MM on HSPCs and their supporting microenvironment.
• To identify molecular mechanisms underlying hematopoietic impairment in MM.
• To assess the reversibility of HSPC dysfunction in MM.

Main Methods:

• Genomic profiling of HSPC subsets from MM patients.
• Functional assays assessing HSPC proliferation, colony formation, self-renewal, migration, and adhesion.
• Measurement of TGFβ levels in BM extracellular fluid.
• Co-culture experiments with mesenchymal stromal cells (MSCs) and HSPCs.
• In vivo transplantation studies in NOG mice.

Main Results:

• MM HSPCs showed deregulated TGFβ signaling, cytoskeletal organization, migration, adhesion, and cell-cycle pathways.
• Activated TGFβ signaling impaired HSPC proliferation, colony formation, and self-renewal.
• Elevated BM TGFβ levels correlated with reduced MSC capacity to support hematopoiesis; TGFβ blockade restored HSPC function.
• MM HSPCs exhibited defective actin assembly and CD44 downregulation, leading to impaired migration and adhesion.
• Transplantation studies revealed enhanced engraftment and normal differentiation of MM HSPCs in a myeloma-free environment, suggesting reversible functional impairment.

Conclusions:

• Hematopoietic suppression in MM stems from HSPC dysfunction driven by MM-associated microenvironmental changes.
• TGFβ signaling and altered cell adhesion/migration are key mechanisms of HSPC impairment in MM.
• The functional deficits in MM HSPCs are reversible upon removal of MM-specific microenvironmental cues.