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Novel gapmers targeting HOXB-AS3 for Acute Myeloid Leukemia Treatment

College of Medicine (COM)
Garzon, Ramiro
Dorrance, Adrienne
Kauppinen, M.Sc., Ph.D., Sakari
Lee, Robert
Papaioannou, Dimitrios
Licensing Manager
Ezzell, Janel
(614) 292-5253

T2017-099 A novel treatment for acute meloid leukemia.

The Need

The expression of long non-coding RNAs (lncRNAs) in older adults with cytogenetically normal acute myeloid leukemia (CN-AML) is reported to have prognostic significance. lncRNA HOXB-AS3 was identified among the top up-regulated lncRNAs in NPM1-mutated CN-AML cases. Aberrant expression of HOX genes is associated with NPM1-mutations in AML and HOX-related lncRNAs have been reported to regulate HOX genes. Accordingly, HOXB-AS3 is believed to bear a functional role in this disease setting and is a novel target for treatment.

The Technology

The Ohio State University researchers, led by Dr. Ramiro Garzon, have discovered that acute myeloid leukemia (AML) patients with nucleophosmism (NPM1) mutations exhibit high expression of a non-coding RNA called HOXBAS3. The researchers studied the functional consequences of this lncRNA in cell lines and primary AML samples by blocking or repressing the expression of this lncRNA using novel locked nucleic acid (LNA) gapmer technology. Results demonstrate HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. Treatment of patient derived xenografts with anti-HOXB-AS3 gapmers led to significantly prolonged median survival (63 vs >100 days). Interrogation of the molecular mechanisms revealed HOXB-AS3 interacts with the ErbB3-binding protein 1 (EBP1) and guides EBP1 to the ribosomal DNA locus. Via this mechanism, HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. These results suggest that in the context of NPM1mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.

Commercial Applications

  • Acute Myeloid Leukemia treatment
    • NPM1-mutated, cytogenetically normal AML (CN-AML)