hematology-2018-posters-abstracts

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August 23-24, 2018 | London, UK

Hematology and Oncology

International Conference on

Journal of Hematology and Blood Disorder | Volume 2

miRNAs Modulate Chemotherapeutic Sensitivity in a model of Acute Myeloid Leukemia

Brian D Adams

Yale School of Medicine, USA

substantial number of chemo-refractory Hematological

malignancies involve CNS localization, causing impairments

in cognitive function as well as enhanced co-morbidities

associated with tumour infiltration into the brain parenchyma.

Identifying therapeutic strategies that reduces CNS infiltration

would greatly improve leukemic patient outcomes, as those

with Hematological malignance absent of CNS localization

are responsive to various chemotherapeutic agents such

as rituximab. Noncoding RNAs play an important role in

regulating the cellular pathways that modulate responses

to chemotherapeutic agents. Therefore, we performed a

microRNA (miRNA) gain-of function screen to identify miRNA(s)

that function as drivers of chemotherapeutic resistance. Using

HL-60 cells, a drug-sensitive acute myeloid leukemia (AML) cell

line,we identifiedcertainmiRNAs fromapool of >400ofmiRNAs

as robust drivers of resistance to the chemotherapeutic agents

cytarabine (Ara-c) and daunorubicin (DNR). Forced expression

of these miRNAs in HL-60 cells decreased DNR- and Ara-c-

induced cell death. Furthermore, HL-60 cells expressing high

levels of these miRNAs proliferated at slower rates than those

without the miRNA. Out of the miRNAs tested, miRNAs that

drive chemotherapeutic resistant also induced a quiescence-

like phenotype, as determined by CFSE staining experiments, by

assessing direct miRNA targets such as CCDN2, the modulation

of which results in an increased frequency of cells in G1. This in

vitro data is supported by the finding that high levels of these

miRNAs in AML clinical samples correlated with poorer overall

survival (OS). Therefore, we argue that miRNAs can functions

as a diagnostic marker in AML patients, and specifically as a

predictor of chemotherapeutic response. These findings are

the basis for ongoing studies elucidating the role of miRNAs

within Hematological malignancies involving CNS localization.