Contribution of an Aged Microenvironment to Aging-Associated Myeloproliferative Disease

The molecular and cellular mechanisms of the age-associated increase in the incidence of acute myeloid leukemia (AML) remain poorly understood. Multiple studies support that the bone marrow (BM) microenvironment has an important influence on leukemia progression. Given that the BM niche itself undergoes extensive functional changes during lifetime, we hypothesized that one mechanism for the age-associated increase in leukemia incidence might be that an aged niche promotes leukemia progression. The most frequent genetic alteration in AML is the t(8;21) translocation, resulting in the expression of the AML1-ETO fusion protein. Expression of the fusion protein in hematopoietic cells results in mice in a myeloproliferative disorder. Testing the role of the age of the niche on leukemia progression, we performed both transplantation and in vitro co-culture experiments. Aged animals transplanted with AML1-ETO positive HSCs presented with a significant increase in the frequency of AML-ETO positive early progenitor cells in BM as well as an increased immature myeloid cell load in blood compared to young recipients. These findings suggest that an aged BM microenvironment allows a relative better expansion of pre-leukemic stem and immature myeloid cells and thus imply that the aged microenvironment plays a role in the elevated incidence of age-associated leukemia

Model for the influence of an aged microenvironment on leukemia progression.

<p>(<b>A</b>) The standard model describes leukemia development as the clonal evolution of an aberrant clone: a founder cell mutates through multiple subsequent steps, frequently via a chronic phase (CML) to ultimately result in acute myeloid leukemia (AML). The velocity of expansion of the aberrant clone increase along the three phases of leukemia (pre-leukemia, chronic leukemia, acute leukemia). The transitions between the phases are not well described in both cellular and molecular terms, but might be caused by intrinsic/genetic and/or extrinsic changes (figure adapted from ref. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031523#pone.0031523-Nowell1" target="_blank">[46]</a>). (<b>B</b>) An aged microenvironment increases the velocity of the expansion of an aberrant pre-leukemic clone. The faster expansion of myeloproliferation-initiating stem cells in aged BM thus promoting the leukemic process. In a larger aberrant cell population, the probability of generating additional hits is increased, resulting in a more likely and thus earlier transition to the next phase of leukemia.</p

<i>In vitro</i> culture of AML1-ETO positive stem/progenitor cells on aged and young endosteal cells.

<p>(<b>A</b>) Experimental set-up for isolation of a cell fraction close to the endosteum ( =  endosteal cells) and representative phase contrast images (×10) from adherent endosteal cells from young and aged mice, bar represent 50 µm (<b>B</b>) Experimental set-up for co-culture experiments and FACS analysis for analysis of the Lin−,Sca-1+, c-Kit+ (LSK) cell compartment. (<b>C</b>) Frequency of GFP+ cells among all cells, (<b>D</b>) frequency of GFP+ cells in the LSK population (<b>E</b>) and the total number GFP+LSK cells. n = 3, * = p<0.05. Bars represent the mean ± SEM.</p