Improve Hematopoiesis by Blocking Protein in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) begins in the bone marrow but often spreads to the blood. AML evolves as a hematopoietic precursor cell undergoes a series of genetic changes. Normal hematopoietic growth and differentiation are disrupted, resulting in an accumulation of rare, immature myeloid cells in the bone marrow and peripheral blood. AML cells have been shown in mice to suppress stable hematopoietic stem and progenitor cells (HSPCs). A new study shows how secreted cell factors, specifically the protein transforming growth factor beta 1 (TGF1), cause hematopoiesis to break down in humans. TGF1 inhibition can boost hematopoiesis in AML patients, according to the findings.

Their results are detailed in a paper published in the journal STEM CELLS titled, “Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells.”

The researchers wrote, “AML is characterized by an expansion of leukemic cells in the bone marrow (BM) and a parallel reduction of normal hematopoietic precursors, resulting in hematopoietic insufficiency, but the underlying mechanisms are poorly understood in humans.” “We exposed healthy BM-derived CD34+ HSPCs to cell-free supernatants derived from AML cell lines as well as from 24 newly diagnosed AML patients, assuming that leukemic cells functionally inhibit healthy CD34+ HSPCs through humoral factors.”

The researchers at Heinrich-Heine-University Düsseldorf wanted to see whether fluids secreted by leukemic cells could be preventing healthy HSPCs from growing.

“Experiments on secretory mechanisms using conditioned media (CM) from AML cells have been done before, but mostly in mice. “We focused on the relationship between leukemic cells and healthy HSPCs using an in vitro method modeling the in vivo situation of bone marrow infiltration by AML cells in order to gain new insights into how this plays out in humans,” said Thomas Schroeder, MD, PhD, of the department of hematology, oncology, and clinical immunology.

“Based on previous studies, we concentrated on secreted factors from AML cells as a major mechanism causing hematopoietic failure,” the researchers wrote. “Our findings show that AML cells impair healthy hematopoietic cells' cell production, cell cycle, colony-forming ability, and, in particular, erythroid differentiation. A particular gene expression signature expressed this functional deficiency at the molecular level. TGF1 was identified as an important trigger factor and potential therapeutic target by molecular and functional analyses.”

Good CD34+ HSPCs were significantly inhibited in proliferation, cell cycling, colony forming, and differentiation when exposed to AML-derived supernatants, according to their findings.

“Blocking the TGF1 pathway with a TGF1 inhibitor like SD208 is something that could be done pharmacologically. Our findings suggest that this may be a promising strategy for improving hematopoiesis in AML patients, according to Schroeder.

“Finding factors for potential intervention in the perplexing issue of AML cells suppressing normal hematopoiesis is highly important,” said Jan Nolta, PhD, editor-in-chief of STEM CELLS. Targeting TGF1 to enable normal stem and progenitor cells to grow is a promising direction for future treatments.”