Persistent altered fusion transcript splicing identifies RUNX1-RUNX1T1+ AML patients likely to relapse.
In acute myeloid leukemia (AML) mouse models, the RUNX1-RUNX1T1 fusion protein has failed to produce leukemia by itself, but alternative splicing of exon 9a of the RUNX1-RUNX1T1 fusion transcript (FT) has recently been shown to enhance the leukemogenic potential. We have analyzed 138 diagnosis and follow-up samples from 13 RUNX1-RUNX1T1+ patients as well as diagnosis samples from 13 RUNX1-RUNX1T1- AML patients and 26 healthy donors. Levels of native RUNX1T1 mRNA were low in both healthy and RUNX1-RUNX1T1-negative AML samples. Likewise, the ratio between RUNX1T1 mRNA harboring exon 9a and lacking exon 9a was low and tightly regulated (0.017-0.11). In contrast, 11/13 RUNX1-RUNX1T1-positive AML patients displayed high and variable ratios of FT ranging from 0.05 to 0.46 (P < 0.001, Wilcoxon rank-sum test), indicating altered exon 9a splicing in these patients. Importantly, patients who remained in continuous complete remission displayed a faster disappearance of the RUNX1-RUNX1T1 exon 9a splice variant compared to patients bound to relapse (P = 0.02). In conclusion, alternative splicing seems to be part of the leukemogenic process in the majority of RUNX1-RUNX1T1-positive AML patients, and splice variant kinetics under cytoreduction may be a predictor for patients prone to relapse.
Ommen
Hans B
HB
Laboratory of Immunohematology, Department of Hematology, Aarhus University Hospital, Arhus, Denmark.
Ostergaard
Mette
M
Yan
Ming
M
Braendstrup
Karin
K
Zhang
Dong-Er
DE
Hokland
Peter
P
D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis* / Q000235:genetics; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012326:RNA Splicing; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D012008:Recurrence; D012074:Remission Induction; D017384:Sequence Deletion; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D014157:Transcription Factors