Impact of the senescent bone marrow microenvironment in AML biology

Project Summary
Acute myeloid leukemia (AML) is the most common diagnosed adult leukemia, the median age of patients with
AML is about 70 years. Although the prognosis for younger adults with AML has improved during the last four
decades, there has been little progress in the treatment of older adults. Currently, approximately 90% of adults
with AML over the age of 55 will die due to resistance to therapy, relapse, or complications from harsh treatments
such as chemotherapy. AML disease progression is heavily influenced by supportive cells in the tumor
microenvironment. Bone marrow mesenchymal stromal cells (BMSCs) are an instrumental extrinsic component
to normal hematopoiesis which are hijacked by leukemic cells in the process of leukemia development. Based
on AML being mainly a disease of older adults and evidence of an accelerated aging phenotype in the (BM)
microenvironment of AML, this proposal aims to investigate the role of aging and senescence in AML disease
progression and to ultimately identify therapeutic targets and eliminate the leukemia-supportive aging phenotype
in the BM. Although epigenetic aging and senescence are two distinct but parallel mechanisms of aging, they
have been shown to converge where certain triggers of senescence can affect epigenetic age. The molecular
basis for age-related alterations in AML-derived BMSCs are poorly described and if deciphered, could have
significant implication on both the prevention and treatment of elderly AML. Moreover, the correlation of
epigenetic age in cells of the AML tumor microenvironment with outcome has not been examined. Thus, the
specific aims of this proposal are to (1) examine epigenetic, transcriptional and phenotypic differences in BMSCs
derived from AML patients, compared to age matched control BSMCs, enabled by the use of methylation studies,
sequencing, mass cytometry and biochemical assays (2) determine the epigenetic age via methylation analysis
of different components of the tumor microenvironment (T-cells, tumor cells and BMSC cells) in AML patient
samples and correlate with disease outcome and finally, (3) utilize findings and techniques developed in aim 1
and 2 to study the status of epigenetic aging and senescence in in vitro and in vivo models of accelerated aging
and relapse to determine if they can be therapeutically targeted. The completion of this work will potentially
provide a quantitative measure of senescence in elderly AML patients, further enhance risk stratification, and
will help identify novel age-related targets in AML-BMSC with potential to lead to development of new therapies.

Grant Number: 5R00CA246083-06
NIH Institute/Center: NIH
Principal Investigator: Amina Abdul-Aziz