Deletions of the transcription factor Ikaros in myeloproliferative neoplasms.
Transformation to acute leukemia is a major complication of myeloproliferative neoplasms (MPNs), however, the genetic changes leading to transformation remain largely unknown. We screened nine patients with post-MPN leukemia for chromosomal aberrations using microarray karyotyping. Deletions on the short arm of chromosome 7 (del7p) emerged as a recurrent defect. We mapped the common deleted region to the IKZF1 gene, which encodes the transcription factor Ikaros. We further examined the frequency of IKZF1 deletions in a total of 29 post-MPN leukemia and 526 MPN patients without transformation and observed a strong association of IKZF1 deletions with post-MPN leukemia in two independent cohorts. Patients with IKZF1 loss showed complex karyotypes, and del7p was a late event in the genetic evolution of the MPN clone. IKZF1 deletions were observed in both undifferentiated and differentiated myeloid cell types, indicating that IKZF1 loss does not cause differentiation arrest but rather renders progenitors susceptible to transformation, most likely through chromosomal instability. Induced Ikzf1 haploinsufficiency in primary murine progenitors resulted in elevated Stat5 phosphorylation and increased cytokine-dependent growth, suggesting that reduced expression of IKZF1 is sufficient to perturb growth regulation. Thus, IKZF1 loss is an important step in the leukemic transformation of a subpopulation of MPN patients.
Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
R
R
Jäger
H
H
Gisslinger
F
F
Passamonti
E
E
Rumi
T
T
Berg
B
B
Gisslinger
D
D
Pietra
A
A
Harutyunyan
T
T
Klampfl
D
D
Olcaydu
M
M
Cazzola
R
R
Kralovics
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D017353:Gene Deletion; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D053614:Janus Kinase 2 / Q000235:genetics; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism
D014408:Biomarkers, Tumor; C497239:IKZF1 protein, human; D012333:RNA, Messenger; D053628:Receptors, Thrombopoietin; D050799:STAT5 Transcription Factor; C082218:MPL protein, human; D051740:Ikaros Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2