del(12)(q24q24) SETD1B/GTF2H3

2014-11-01   Lisa Pieri , Chiara Paoli , Giulia Daniele , Terra Lasho , Ayalew Tefferi , Alessandro M. Vannucchi , Clelia Tiziana Storlazzi 

1.Department of Biology, University of Bari, bari, Italy (CTS, GD); Department of Experimental, Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy (LP, CP, AMV); Mayo Clinic, Hematology (TL, AT).


We identified a novel SETD1B/GTF2H3 fusion gene in a polycythemia vera (PV) patient with complex karyotype, harboring a cryptic deletion involving chromosome band 12q24.31. This rearrangement led to the juxtaposition of the SETD1B (SET domain containing 1B) gene at intron 11 (chr12:122,257,801) with the GTF2H3 (general transcription factor IIH, polypeptide 3) gene at intron 5 (chr12:124,137,254). In silico translation showed a protein retaining SETD1B RNA binding domain (RRM_S) at its N-terminus and a portion of GTF2H3 DNA binding domain (Tfb4) at its C-terminus. We also provided evidences that SETD1B might be rearranged in an additional PV case, although in a small proportion of hematopoietic cells, indicating a possible role of SETD1B in disease pathogenesis.

Clinics and Pathology


Polycythemia Vera


Myeloproliferative neoplasm

Phenotype stem cell origin

CD34+ cell


SETD1B is a SET-domain containing protein with histone H3-Lys4 methyltransferase activity, which is associated with active gene expression (Lee et al. 2007). SET-like enzyme genes include those implicated in various leukemias and cancers like MLL. SETD1B interacts with RBM15 through its LSD motif, creating a complex important for epigenetic regulation (Lee et al. 2002). RBM15 (RNA binding motif protein 15) utilizes the epigenetic mechanism to control alternative splicing of MPL (myeloproliferative leukemia virus oncogene), leading to the regulation of thrombopoietin response in hematopoietic stem cells (Xiao et al. 2014). In the SETD1B/GTF2H3 chimeric protein, SETD1B loses the LSD domain, possibly leading to an altered epigenetic regulation. GTF2H3 has been related to the nucleotide excision repair pathway, and resulted upregulated in HL-60 cell line resistant to ATRA (Liu et al. 2014).


The SETD1B/GTF2H3 rearrangement was found in only one out of 60 patients with myeloproliferative neoplasms evaluated. However, FISH analysis revealed a splitting signal in a very low percentage of nuclei (3/412, 0.7%) in one of 13 analyzed patients, suggesting a possible rearrangement of SETD1B with other partner genes (Storlazzi et al. 2014).


The SETD1B/GTF2H3 rearrangement has been found in a patient diagnosed with Polycythemia Vera that evolved in post-polycythemia vera myelofibrosis after two years.


Blood smear showed no leukoerythroblastic picture but only few dacrocytes.


The bone marrow biopsy showed the presence of hyperplasia of myeloid and erythroid lineages, increased scattered megakaryocytes without overt morphologic abnormalities and an increase in reticulin fibrosis compatible with grade 1 of 3 (european scale).


The subject was treated with phlebotomies and hydroxyurea according to the European Leukemia Net (ELN) recommendations (Barbui et al. 2011), but considered as refractory/resistant to hydroxyurea (Barosi et al. 2010). The patient was then enrolled in a clinical trial with the histone deacethylase inhibitor givinostat, obtaining prompt relief from pruritus and rapid reduction up to stop of phlebotomies (Finazzi et al. 2013). However, the treatment was interrupted after six months because of progression of a pre-existing mild renal insufficiency, and the subject was shifted again to low-dose hydroxyurea plus phlebotomies.


Two years after the detection of the SETD1B/GTF2H3 fusion gene, the patient was diagnosed with post polycythemia vera myelofibrosis according to the diagnostic criteria of the International Working Group for Myeloproliferative Disorders Research and Treatment (IWG-MRT) (Barosi et al, 2008). At that time, the gene fusion was still detectable in bone marrow sample.



The rearrangement leading to the genesis of this fusion gene (a cryptic deletion on chromosome 12) was not evident at cytogenetic level.

Cytogenetics morphological

The only described PV patient harboring this novel fusion gene showed a complex karyotype.

Cytogenetics molecular

The SETD1B/GTF2H3 fusion gene was identified by genomic massive sequencing. FISH analysis with an appropriate probe set for SETD1B disclosed the occurrence of a 110Kb interstitial deletion, confirming the gene rearrangement.
Atlas Image
Partial karyotype of the patient with del(12) (lower panel), showing FISH analysis performed by using three BAC clones encompassing the SETD1B gene region (upper panel). The colored rectangles (blue, red, and green) correspond to the results obtained respectively for probes RP11-1065O14, RP11-7M8, and RP11-87C12. The deletion breakpoint in the patient was mapped within RP11-7M8, as its signal intensity on the deleted chromosome 12 [del(12)] was significantly fainter than the one on the normal homolog. RP11-1066D14 was retained on del(12), while RP11-87C12 was deleted on del(12).

Additional anomalies

A ins(6;15) insertion accompanied by chromosome losses at all the breakpoint regions [6p22.1p22.3 (11,6 Mb), 15q21.3q22.2 (6 Mb), and 15q25.1q25.2 (3 Mb)]; a cryptic and inverted insertion of a short chromosome 15q25.1 fragment (chr15:79,476,511-79,486,994) into chromosome 18, accompanied by a 25.7 Kb heterozygous deletion

Genes Involved and Proteins

Gene name
SETD1B (SET domain containing 1B)
Dna rna description
Homo sapiens SET domain containing 1B (SETD1B
Protein description
SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4.
Gene name
GTF2H3 (general transcription factor IIH subunit 3)
Dna rna description
Homo sapiens general transcription factor IIH, polypeptide 3. The gene encodes for four transcript variants.
Protein description
GTF2H3 is a subunit of the core-TFIIH basal transcription factor. It localizes to the nucleus and is involved in RNA transcription and nucleotide excision repair. Moreover, it associates with the Cdk-activating kinase complex.

Result of the Chromosomal Anomaly


5 SETD1B/3 GTF2H3. SETD1B (accession no. NM_015048) at exon 11 was fused in frame with GTF2H3 (accession no. NM_001516) at exon 7.

Detection protocole

Genomic paired-end massive sequencing. The fusion transcript was validated by RT-PCR and Sanger sequencing.
Atlas Image
Wild-type SETDB1 (grey), GTF2H3 (blue) and chimeric SETD1B/GTF2H3 predicted proteins, accordingly to ORF finder and BlastP analyses of the full-length transcripts. Red arrows indicate the breakpoints, respectively in SETD1B (Accession no. NP_055863, aminoacid no.1260), and in GTF2H3 (Accession no. NP_001507, aminoacid no.153). RRM_S: RNA recognition motif; N-SET, SET: catalytic domains for H3K4 trimethylation; P: cystein-rich motif; TBF4: transcription factor with DNA binding domain.


In silico translation of the fusion transcript, obtained by ORF finder, showed a putative protein maintaining the SETD1B RNA binding domain (RRM_S) at its N-terminus and a portion of GTF2H3 DNA binding domain (Tfb4) at its C-terminus


Pubmed IDLast YearTitleAuthors
212057612011Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.Barbui T et al
199301822010A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process.Barosi G et al
177287872008Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment.Barosi G et al
235739502013A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy.Finazzi G et al
229279432012Rbm15-Mkl1 interacts with the Setd1b histone H3-Lys4 methyltransferase via a SPOC domain that is required for cytokine-independent proliferation.Lee JH et al
173559662007Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex.Lee JH et al
249930142014Distinguishing between cancer cell differentiation and resistance induced by all-trans retinoic acid using transcriptional profiles and functional pathway analysis.Liu SM et al
243827382014Complex karyotype in a polycythemia vera patient with a novel SETD1B/GTF2H3 fusion gene.Tiziana Storlazzi C et al
254685692015Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-Mpl.Xiao N et al


Lisa Pieri ; Chiara Paoli ; Giulia Daniele ; Terra Lasho ; Ayalew Tefferi ; Alessandro M. Vannucchi ; Clelia Tiziana Storlazzi

del(12)(q24q24) SETD1B/GTF2H3

Atlas Genet Cytogenet Oncol Haematol. 2014-11-01

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