MicroRNA Profiles of the Bone Marrow Microenvironment and Serum in Multiple Myeloma Reveal Micrornas in the Serum Associated with Myeloma
Katherine R Calvo, Weixin Wang, Meghan Corrigan-Cummins, Adriana Zingone, Rene Costello, Neha Korde, Irene Ghobrial, Ola Landgren. NIH Clinical Center, Bethesda, MD; National Cancer Institute, Bethesda, MD; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Background: Multiple myeloma (MM) is a plasma cell neoplasm, which may derive important survival signals from the bone marrow microenvironment. MicroRNA (miR) represents a unique mechanism of post-transcriptional gene regulation that plays important roles in cancer, including MM. miRs can be readily detected in bone marrow supernatant, stromal cell exosomes, and in peripheral blood. miRs from the bone marrow microenvironment which are released to the peripheral blood may be useful as biomarkers or targets for drug therapy.
Design: Bone marrow and blood were collected from 20 patients with MM and 8 healthy controls. RNA was isolated and analyzed using high density microRNA arrays containing over 860 human miR sequences. The array data were normalized to the data point of 75 percentile signal strength and to a set of spike-in and control probes, respectively. The differences between the means of MM and control groups were analyzed by Mann-Whitney rank sum test. miRs with significant p values (p ≤ 0.05 or 0.01) and fold change (≥ 2-fold) in both normalization methods were selected for further analysis.
Results: In bone marrow supernatant (BM), 111 miRs were significantly differentially expressed (> 2-fold; p < 0.05) in MM in comparison to controls. 42 miRs were increased in BM and 69 miRs were decreased. Hierarchical clustering analysis revealed a unique signature comprised of 32 miRs capable of differentiating controls from MM cases in BM. In the peripheral blood (PB), 171 miRs were significantly differentially expressed in MM (> 2-fold; p < 0.01). 117 miRs were increased and 54 miRs were decreased in PB. Among the 32 miRs comprising the MM BM signature that differentiated MM from controls, 15 were also differentially expressed in PB. Six of these miRs showed significantly decreased expression in both BM and PB (let-7a, -7b; miR-20a, -15a, -21, -19b) while the remaining nine miRs showed increased expression (miR-575, -939, -940, -1237, -1234, -1238, -583, -498, -602).
Conclusions: The bone marrow microenvironment in MM shows a unique miR signature which is also partially present in the peripheral blood. Several of the miRs identified are known to be involved in regulation of cell proliferation and survival and may be promising candidate serum biomarkers for monitoring MM tumor burden, response to therapy, or potentially as drug targets.
Tuesday, March 20, 2012 9:00 AM
Platform Session: Section C, Tuesday Morning