Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models
N Kato, J Kitaura, N Doki, Y Komeno… - Blood, The Journal …, 2011 - ashpublications.org
Blood, The Journal of the American Society of Hematology, 2011•ashpublications.org
Two types of mutations of a transcription factor CCAAT-enhancer binding protein α (C/EBPα)
are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal
mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine
zipper domain. Our results showed that a mutation of C/EBPα in one allele was observed in
AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike
an N-terminal frame-shift mutant (C/EBPα-Nm)–transduced cells, a C-terminal mutant …
are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal
mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine
zipper domain. Our results showed that a mutation of C/EBPα in one allele was observed in
AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike
an N-terminal frame-shift mutant (C/EBPα-Nm)–transduced cells, a C-terminal mutant …
Abstract
Two types of mutations of a transcription factor CCAAT-enhancer binding protein α (C/EBPα) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBPα in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBPα-Nm)–transduced cells, a C-terminal mutant (C/EBPα-Cm)–transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBPα-Cm collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBPα-Cm strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBPα-Cm failed to inhibit transcriptional activity of wild-type C/EBPα, it suppressed the synergistic effect between C/EBPα and PU.1. On the other hand, C/EBPα-Nm inhibited C/EBPα activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBPα-Nm. Thus, 2 types of C/EBPα mutations are implicated in leukemo-genesis, involving different and cooperating molecular mechanisms.
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