Down-regulation of microRNAs 222/221 in acute myelogenous leukemia with deranged core-binding factor subunits

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• Core-binding factor leukemia (CBFL), a subset of acute myeloid leukemia (AML), is defined by specific genetic mutations.
• Increased cell proliferation and inhibited apoptosis, often involving the KIT receptor, are key in CBFL leukemogenesis.
• High KIT expression is a common characteristic of CBFL, suggesting a link to underlying genetic alterations.

Purpose of the Study:

• To investigate the role of microRNA (MIR) 222/221 as a potential link between core-binding factor (CBF) mutations and KIT receptor overexpression in CBFL.
• To elucidate the regulatory mechanism by which CBF-associated fusion proteins influence MIR-222/221 expression and subsequently affect KIT levels.

Main Methods:

• Analysis of MIR-222/221 expression in normal bone marrow progenitor cells and CBFL patient samples.
• Investigation of KIT (CD117) expression levels in relation to CBF rearrangements (t(8;21) or inv(16)).
• Functional studies using reporter assays and a mouse cell model (32D/WT1) to assess the impact of CBF fusion proteins on MIR-222/221 promoter activity and KIT expression.

Main Results:

• MIR-222/221 expression is upregulated during normal myeloid differentiation.
• CBFL blasts with CBF rearrangements and high KIT expression show significantly lower MIR-222/221 levels compared to non-CBFL blasts.
• CBF-associated fusion proteins (AML1-MTG8 and AML1-MTG16) bind the MIR-222/221 promoter and repress its transcription, leading to MIR-222/221 down-regulation and concomitant KIT up-regulation.

Conclusions:

• CBFL-associated fusion proteins contribute to leukemogenesis by down-regulating MIR-222/221.
• This down-regulation of MIR-222/221 leads to the up-regulation of the KIT receptor.
• The findings provide a molecular mechanism explaining the frequent co-occurrence of CBF genetic rearrangements and KIT overexpression in AML.