Bone marrow failure due to acute myeloid leukemia (AML) is a significant factor behind the disease’s high rate of morbidity and mortality. Previous studies in mice suggest that AML cells inhibit healthy hematopoietic (blood) stem and progenitor cells (HSPC). Although AML makes up only about 1% of all cancers, it is the second most common type of leukemia diagnosed, according to the American Cancer Society. AML affects the blood and bone marrow – the spongy tissue inside bones where blood cells are made. The mortality rate is high – for those aged 20 and older, the five-year survival rate is a dismal 26%. The mechanisms by which AML develops are not completely understood, but it is generally believed to begin in the hemopoietic stem cells or progenitors.
These develop into myeloid cells and in turn go on to become red blood cells, white blood cells or platelets. But if some genetic mechanisms (e.g. gene mutation, transcription or translation) get altered, the stem cell can become malignant. A study released in the journal Stem Cells adds to this extent of knowledge by showing how secreted cell factors, in particular a cytokine called transforming growth factor beta 1 (TGFβ1), leads to a breakdown in the production of healthy blood cells in humans. The study’s findings indicate that blocking TGFβ1 could improve hematopoiesis in AML patients. This latest study, by researchers at Heinrich-Heine-University Düsseldorf, was designed to investigate what role fluids secreted by leukemic cells might play in inhibiting the growth of healthy hematopoietic stem and HSPC.
The notion that TGF-beta may drive impairments in the functioning of bone marrow during leukemia is not new. Scientists have explored several aspects of TGFbeta-driven gene expression and the products in terms of cytokines, growth factors, cellular signaling and humoral or surface factors interacting among the normal and malignant cells. Malignant clonal expansion in leukemia is accompanied with pauperization of marrow cellularity; even in pre-leukemic stages (myelodysplasia) histology shows that while normal progenitors shrink in number, fibroblasts and other kind of cells rise. Fibroblasts are stimulated to duplicate in response to TGF-beta1 and this explains while the sick marrow become stiffened and emptied (myelofibrosis). Lately, scientists have proved that the CXCL12/CXCR4 chemokine axis is pivotal in the interactions between the stroma and the anomalous progenitors.
Thomas Schroeder, MD, PhD, Study Corresponding Author, Department of Hematology, Oncology and Clinical Immunology, AlphaMed Press, explained the experiments: “Experiments using conditioned media from AML cells to address secretory mechanisms have been performed before, but mainly in mice. In order to gain new insights into how this plays out in humans, we focused on the interaction between leukemic cells and healthy progenitors using an in vitro system modeling the in vivo situation of bone marrow infiltration by AML cells. This was accomplished by exposing healthy bone marrow-derived CD34+ progenitors to supernatants derived from AML cell lines and newly diagnosed AML patients. (CD34 is a marker of human HSC, while supernatants are the products secreted by cells).”
He continued: “Our findings revealed that exposure to AML-derived supernatants significantly inhibited proliferation, cell cycling, colony formation and differentiation of healthy CD34+ stem cells Further experiments determined that leukemic cells induce functional inhibition of healthy HSPC, at least in part through TGFβ1. Blocking the TGFβ1 pathway is something that could be pharmacologically accomplished with a TGFβ1 inhibitor such as SD208. Our data indicate this could be a promising approach to improve hematopoiesis in AML patients. The possibility of targeting TGFβ1 in order to allow the normal stem and progenitor cells to expand is a promising lead toward future treatments”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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