Publication — IRIC

HMGA2 expression defines a subset of human AML with immature transcriptional signature and vulnerability to G2/M inhibition.

High-mobility group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein that is normally expressed in stem cells of various tissues and aberrantly detected in several tumor types. We recently observed that one-fourth of human acute myeloid leukemia (AML) specimens express HMGA2, which associates with a very poor prognosis. We present results indicating that HMGA2+ AMLs share a distinct transcriptional signature representing an immature phenotype. Using single-cell analyses, we showed that HMGA2 is expressed in CD34+ subsets of stem cells and early progenitors, whether normal or derived from AML specimens. Of interest, we found that one of the strongest gene expression signatures associated with HMGA2 in AML is the upregulation of G2/M checkpoint genes. Whole-genome CRISPR/Cas9 screening in HMGA2 overexpressing cells further revealed a synthetic lethal interaction with several G2/M checkpoint genes. Accordingly, small molecules that target G2/M proteins were preferentially active in vitro and in vivo on HMGA2+ AML specimens. Together, our findings suggest that HMGA2 is a key functional determinant in AML and is associated with stem cell features, G2/M status, and related drug sensitivity.

Publication date
août 23, 2022
Principal Investigators
Moison C, Spinella JF, Chagraoui J, Lavallée VP, Lehnertz B, Thiollier C, Boivin I, Mayotte N, MacRae T, Marinier A, Hébert J, Sauvageau G
PubMed reference
Blood Adv 2022;6(16):4793-4806
PubMed ID
35797243
Affiliation
The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.