Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia
Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia
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BioRxiv. 29 December 2023. https://doi.org/10.1101/2023.12.29.573601. Online ahead of print. PDF |
ABSTRACT
Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by 31
oncogenic translocations. In the case of chronic myelogenous leukemia (CML) the BCR-ABL fusion initiates 32
chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been 33
transformative for CML, blast crisis CML remains relatively drug resistant. Here we show that MSI2-HOXA9, 34
a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to 35
BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, 36
increased lethality and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed 37
that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML 38
relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream 39
changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-40
HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-41
HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase Polrmt and augmenting 42
mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first 43
time that translocations involving the stem and developmental signal MSI2 can be oncogenic, and suggest that 44
MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation 45
across solid cancers.
oncogenic translocations. In the case of chronic myelogenous leukemia (CML) the BCR-ABL fusion initiates 32
chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been 33
transformative for CML, blast crisis CML remains relatively drug resistant. Here we show that MSI2-HOXA9, 34
a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to 35
BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, 36
increased lethality and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed 37
that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML 38
relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream 39
changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-40
HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-41
HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase Polrmt and augmenting 42
mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first 43
time that translocations involving the stem and developmental signal MSI2 can be oncogenic, and suggest that 44
MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation 45
across solid cancers.
