Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts.
Chronic myelomonocytic leukemia is similar to but a separate entity from both myeloproliferative neoplasms and myelodysplastic syndromes, and shows either myeloproliferative or myelodysplastic features. We ask whether this distinction may have a molecular basis. We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples. Analysis of 12 mRNAS from chronic myelomonocytic leukemia established a gene expression signature of 122 probe sets differentially expressed between proliferative and dysplastic cases of chronic myelomonocytic leukemia. As compared to proliferative cases, dysplastic cases over-expressed genes involved in red blood cell biology. When applied to 32 myelodysplastic syndromes, this gene expression signature was able to discriminate refractory anemias with ring sideroblasts from refractory anemias with excess of blasts. By comparing mRNAS from these two forms of myelodysplastic syndromes we derived a second gene expression signature. This signature separated the myelodysplastic and myeloproliferative forms of chronic myelomonocytic leukemias. These results were validated using two independent gene expression data sets. We found that myelodysplastic chronic myelomonocytic leukemias are characterized by mutations in transcription/epigenetic regulators (ASXL1, RUNX1, TET2) and splicing genes (SRSF2) and the absence of mutations in signaling genes. Myelodysplastic chronic myelomonocytic leukemias and refractory anemias with ring sideroblasts share a common expression program suggesting they are part of a continuum, which is not totally explained by their similar but not, however, identical mutation spectrum.
Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, UMR1068 Inserm, Institut Paoli-Calmettes, Marseille, France. gelsiv@marseille.fnclcc.fr
Véronique
V
Gelsi-Boyer
Nathalie
N
Cervera
François
F
Bertucci
Mandy
M
Brecqueville
Pascal
P
Finetti
Anne
A
Murati
Christine
C
Arnoulet
Marie-Joelle
MJ
Mozziconacci
Ken I
KI
Mills
Nicholas C P
NC
Cross
Norbert
N
Vey
Daniel
D
Birnbaum
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D000756:Anemia, Sideroblastic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003937:Diagnosis, Differential; D049308:Dioxygenases; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D000068103:Serine-Arginine Splicing Factors
C473949:ASXL1 protein, human; D018952:Antigens, CD34; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D049308:Dioxygenases; C541081:TET2 protein, human