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Editorials
Figure 1. Schematic representation of the findings by Ingenhag et al.15
implicated in cell-cell interaction and adhesion.18 Interestingly, MNX1 expression also reduced the clono- genic activity of human CD34+ HSPC. Likewise previous experiments also showed no aberrant in vitro clonogenic growth of MNX1 over-expressing mouse HSPC.18 Together, the experiments in mouse and human hematopoietic cells suggest increased MNX1 expression interferes with normal hematopoietic differentiation. Notably, most of the reported infants aberrantly express- ing MNX1 were diagnosed with poorly differentiated FAB subtypes. Four out of 42 published patients developed acute megakaryoblastic leukemia (AMKL) suggesting MNX1 impacts on MEP cell maturation.6
Collectively, Ingenhag et al.15 show that aberrantly expressed MNX1 interferes with normal cycle progres- sion, inducing premature senescence in solid cancer cell lines, and interferes with hematopoietic differentiation in vitro and in vivo (Figure 1).
This work provides important clues for our understand- ing of t(7;12)(q36;p13)+ infant AML and sets the stage for additional experiments addressing several open key ques- tions. First, it remains to be demonstrated whether aber-
rant MNX1 expression is sufficient to induce a leukemic phenotype. Although recent large deep sequencing studies did not report the presence of any common co-operating mutations (FLT3-ITD, NPM1, CEBP/A, WT1) in 4 infant AML carrying t(7;12)(q36;p13), the strong association with trisomy 19 in the blasts of the majority of these patients suggests some co-operative events.19 Notably, trisomy 19 has been described as a recurrent chromosomal abnormal- ity in hematologic malignancies, including AMKL.20,21
Second, it will be important to identify the natural target cell of MNX1-mediated transformation. The exclusive association of t(7;12)(q36;p13) strongly suggests a fetal ori- gin. It is somehow reminiscent of inv(16)(p13q24) leading to expression of a CBFA2T3-GLIS2 fusion in AMKL which mostly affects infants. Modeling the transforming activity of this fusion in mice revealed that only expression in fetal liver hematopoietic cells but not in adult BM-derived cells was able to induce a leukemic disease.22,23 Therefore, future studies will ideally follow different fetal-liver hematopoietic stem and/or progenitor cells conditionally over-expressing MNX1 in clonogenic assays and BM reconstitution assays.
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haematologica | 2019; 104(1)