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miR-17 deregulates a core RUNX1-miRNA mechanism of CBF acute myeloid leukemia

John Adams Fischer1, Stefano Rossetti1, Arani Datta1, Kevin Hasegawa Eng2, Alessandro Beghini3 and Nicoletta Sacchi1

Mol Cancer. 2015; 14(1):7.

1 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo NY 14263, USA.

2 Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo NY 14263, USA.

3 Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan 20133, Italy.


The core binding factor (CBF) complex plays a critical role in hematopoiesis by regulating the expression of both coding and non-coding RNAs. Nonrandom cytogenetic rearrangements involving either one of the CFB subunits, CBF alpha (also known as RUNX1) and CFB beta (CBFB), in myeloid cells define a specific subgroup of acute myelogenous leukemia, the CBF-AML subgroup. In this paper we report that fusion proteins derived by the two most common CBF-AML cytogenetic rearrangements, t(8;21) and inv(16), by interfering with RUNX1 transcriptional function, deregulate a core RUNX1-regulated microRNA mechanism. Deregulation of this mechanism leads to increased KIT receptor-induced proliferation of undifferentiated myeloid cells. Interestingly, in AML lacking RUNX1 and CBFB genetic rearrangements we found that a microRNA (miR-17) which targets RUNX1-3’UTR, by affecting the same RUNX1-regulated microRNA mechanism, recapitulates the biological effects induced by the CBF fusion proteins. Thus, these findings let us expand the concept of CBF-AML to include, in addition to canonical CBF-AML, also AML with deregulation of microRNAs that, like miR-17, target RUNX1.  Most importantly, we found that in normal myeloid cells increasing KIT expression per se delays myeloid cell differentiation in response to cytokines (e.g.  G-CSF cytokine). This delay can be counteracted by an inhibitor of KIT receptor-mediated proliferation. Thus, in normal cells there must be a microRNA machinery which involves both microRNAs that regulate RUNX1 and microRNAs that are regulated by RUNX1 to temporally regulate   cytokine-induced myeloid differentiation by fine tuning the extent of KIT receptor-induced proliferation. Should be this mechanism negatively affected, myeloid cells are expected to remain “stuck” in a proliferative, undifferentiated mode, thus behaving as leukemic cells.

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Figure legend

Scheme showing that microRNAs targeting RUNX1 and targeted by RUNX1 expand the concept of CBF-AML

The t(8;21) and inv(16) chromosome rearrangements  are associated mostly with M2 and M4 CBF-AML subtypes, respectively (left). Upregulation of miR17, detected mostly in  AML M5 subtype (left), by decreasing RUNX1 level, affects the same RUNX1-miRNA core mechanism (right) deregulated either by the RUNX1-MTG8 fusion protein, generated by the  t(8;21), or the CBFB-MYH11, generated by the inv(16). The RUNX1-miRNA core mechanism, involving, among others, miR221 and miR223, coordinates myeloid cell proliferation and differentiation.  The extent of KIT-mediated proliferation influences differentiation of normal myeloid cells. In contrast, not only CBF-AML fusion proteins, but also miR17 upregulation in AML, by interfering with the normal mechanism, sustain KIT-induced proliferation of undifferentiated myeloid cells.

miR-17 deregulates a core RUNX1-miRNA mechanism of CBF acute myeloid leukemia. Global Medical Discovery