Abstract
Simple SummaryThe formation of normal blood cells in the bone marrow is supported by a network of non-hematopoietic cells including connective tissue cells, blood vessel cells and bone-forming cells. These cell types support and regulate the growth of acute myeloid leukemia (AML) cells and communicate with leukemic cells through the release of proteins to their common extracellular microenvironment. One of the AML-supporting normal cell types is a subset of connective tissue cells called mesenchymal stem cells. In the present study, we observed that AML cells release a wide range of diverse proteins into their microenvironment, but patients differ both with regard to the number and amount of released proteins. Inhibition of this bidirectional communication through protein release between AML cells and leukemia-supporting normal cells may become a new strategy for cancer treatment.Extracellular protein release is important both for the formation of extracellular matrix and for communication between cells. We investigated the extracellular protein release by in vitro cultured normal mesenchymal stem cells (MSCs) and by primary human acute myeloid leukemia (AML) cells derived from 40 consecutive patients. We observed quantifiable levels of 3082 proteins in our study; for the MSCs, we detected 1446 proteins, whereas the number of released proteins for the AML cells showed wide variation between patients (average number 1699, range 557–2380). The proteins were derived from various cellular compartments (e.g., cell membrane, nucleus, and cytoplasms), several organelles (e.g., cytoskeleton, endoplasmatic reticulum, Golgi apparatus, and mitochondria) and had various functions (e.g., extracellular matrix and exosomal proteins, cytokines, soluble adhesion molecules, protein synthesis, post-transcriptional modulation, RNA binding, and ribonuclear proteins). Thus, AML patients were very heterogeneous both regarding the number of proteins and the nature of their extracellularly released proteins. The protein release profiles of MSCs and primary AML cells show a considerable overlap, but a minority of the proteins are released only or mainly by the MSC, including several extracellular matrix molecules. Taken together, our observations suggest that the protein profile of the extracellular bone marrow microenvironment differs between AML patients, these differences are mainly caused by the protein release by the leukemic cells but this leukemia-associated heterogeneity of the overall extracellular protein profile is modulated by the constitutive protein release by normal MSCs.
Highlights
Acute myeloid leukemia (AML) is an aggressive malignancy arising from hematopoietic stem cells, and the median age at the time of first diagnosis is 65–70 years [1]
Among the 3026 different proteins released by primary human acute myeloid leukemia (AML) cells, 435 proteins were quantified in AML-Conditioned media (CM) for at least 38 patients (161 expressed in all 40 patients), whereas 415 proteins were quantified in AML-CM for five or fewer patients (98 proteins only in one patient each)
We investigated CD44 release in addition to the Extracellular matrix (ECM) signature proteins because it can bind to a wide range of extracellular matrix molecules [36,37,38,39,40,41,42,43], it seems to be an important normal stem cell regulator in the endothelial niche [43] and it is involved in interactions between AML cells and AML-supporting endothelial cells [42]
Summary
Acute myeloid leukemia (AML) is an aggressive malignancy arising from hematopoietic stem cells, and the median age at the time of first diagnosis is 65–70 years [1]. Acute promyelocytic leukemia (APL) is an AML subtype characterized by specific genetic abnormalities, different treatment and better prognosis than non-APL AML [2]. AML is an aggressive malignancy; the only possibility for cure is intensive chemotherapy, possibly including allogeneic stem cell transplantation. Many elderly and unfit patients can only receive supportive care and have a median survival of 1–3 months after diagnosis [1]. There is a need for more effective and less toxic treatment in AML that can be used in combination with the conventional intensive therapy for younger patients and/or as a less toxic treatment in elderly/unfit patients
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