t(1;9)(p13;p12) PAX5/HIPK1

2014-02-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Clinics and Pathology


B-cell acute lymphoblastic leukemia (B-ALL)


Only one case to date, a 3-year old boy with a CD10+ ALL (Nebral et al., 2009).


The patient was noted at an intermediate risk, and was in complete remission 6 months after diagnosis.

Genes Involved and Proteins

Gene name
HIPK1 (homeodomain interacting protein kinase 1)
Protein description
1210 amino acids (aa). From N-term to C-term, contains a protein kinase domain (aa 190-518), a nucleotide binding motif (aa 196-204), a domain interacting with DAB2IP (AIP1, or AF9q34, 9q33.2) (aa 518-889), a nuclear localization signal (aa 844-847), a region interacting with TP53 (aa 885-1093), a nuclear speckle retention signal (aa 887-992), (corresponding to aa 860-967 in HIPK2), a PEST domain (enriched in proline (P), glutamate (E), serine (S), and threonine (T), expedite the degradation of proteins) (aa 892-972), SUMO interaction motifs, required for nuclear localization and kinase activity (aa 902-926), a domain interacting with DAB2IP/MAP3K5 (aa 973-1209), a histidine-rich region (aa 1086-1154), and a tyrosine-rich region (aa 1175-1209) (YH region). The lysine residues at the sumoylation motifs are the following: K25, K317, K440, K556, and K1202 (Kim et al., 1998; Li et al., 2005; Swiss-Prot).
First identified as a nuclear serine/threonine kinase. Homeodomain-interacting protein kinase. HIPK1 positively or negatively modulate signaling pathways controlling cell proliferation and/or apoptosis (review in Rinaldo et al., 2008). HIPK1 and HIPK2 act cooperatively as corepressors in the transcriptional activation of angiogenic genes, including MMP10 (11q22.2) and VEGFA (6p21.1), that are critical for the early stage of vascular development (Shang et al., 2013). HIPK1 regulates the p53 signaling pathway. PARK7 (also called DJ-1, 1p36.23), a protein also linked to the p53 signaling pathway, is able to induce HIPK1 degradation. HIPK1 directly phophorylates TP53 on its serine-15. Serine 15 phosphorylation induces a rise in CDKN1A (p21, 6p21.2) expression and cell cycle arrest (Rey et al., 2013). HIPK1 phosphorylates DAXX (6p21.32), a protein which interacts with PML (15q24.1), the organizer of nuclear bodies (Ecsedy et al., 2003), and which relocalizes from the nucleus to the cytoplasm in response to stress. During glucose deprivation, a pathway involving MAP3K5 (also called ASK1, 6q23.3), -> MAP2K4 (SEK1, 17p12) -> MAPK8 (JNK1, 10q11.22) -> HIPK1 is activated, and DAXX is relocated in the cytoplasm (Song and Lee, 2003). TNF (TNF-alpha, 6p21.33) induces desumoylation and cytoplasm translocation of HIPK1 leading to apoptosis (Li et al., 2005). HIPK1 and HIPK2 bind HOX genes homeodomains and regulate their expression, as well as PAX1 (20p11.22) and PAX3 (2q36.1) transcription (Isono et al., 2006). HIPK1 and HIPK2 phosphorylates EP300 (22q13.2) and RUNX1 (21q22.12) during embryonic development, and Hipk1/Hipk2-deficient mice show defective definitive hematopoiesis (Aikawa et al., 2006). HIPK1 phosphorylates MYB (6q23.3), a transcriptional activator essential for the establishment of haemopoiesis, and causes repression of MYB activation (Matre et al., 2009). HIPK1 interacts with DVL1 (1p36.33) and TCF3 (E2A, 19p13.3) and regulates Wnt/b-catenin target genes during early embryonic development (Louie et al., 2009). HIPK1 is highly overexpressed in colorectal carcinomas compared with healthy mucosa. The highest peak of HIPK1 expression occurred at early stages and decreased in latter stages. HIPK1 appeared to be induced as a defense mechanism to fight against intern deregulations and stressful conditions, rather than produced by the cancer cells as an indispensable factor for tumor evolution (Rey et al., 2013). HIPK1 is expressed only in invasive breast cancer cells with three different subcellular localization, associated with different tumor histopathologic characteristics (Park et al., 2012).
Gene name
PAX5 (paired box gene 5)
Protein description
391 amino acids; from N-term to C-term, PAX5 contains: a paired domain (aa: 16-142); an octapeptide (aa: 179-186); a partial homeodomain (aa: 228-254); a transactivation domain (aa: 304-359); and an inhibitory domain (aa: 359-391). Lineage-specific transcription factor; recognizes the concensus recognition sequence GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5; activates B-cell specific genes and repress genes involved in other lineage commitments. Activates the surface cell receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007; Medvedovic et al., 2011).

Result of the Chromosomal Anomaly


Fusion of PAX5 exon 5 to HIPK1 exon 9.
Atlas Image
t(1;9)(p13;p13) PAX5/HIPK1 fusion protein.


751 amino acids. The predicted fusion protein contains the DNA binding paired domain of PAX5 and the nuclear localization signal, the region interacting with TP53, the nuclear speckle retention signal, the PEST domain, the SUMO interaction motifs, the domain interacting with DAB2IP/MAP3K5, and theYH region from HIPK1.

Highly cited references

Pubmed IDYearTitleCitations
244351672014Functional heterogeneity of PAX5 chimeras reveals insight for leukemia development.13


Pubmed IDLast YearTitleAuthors
169175072006Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation.Aikawa Y et al
174404522007Pax5: the guardian of B cell identity and function.Cobaleda C et al
125294002003Homeodomain-interacting protein kinase 1 modulates Daxx localization, phosphorylation, and transcriptional activity.Ecsedy JA et al
150040082004Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene.Fuxa M et al
165379182006Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals.Isono K et al
152585792004B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5.Johnson K et al
97482621998Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors.Kim YH et al
157016372005Tumor necrosis factor alpha-induced desumoylation and cytoplasmic translocation of homeodomain-interacting protein kinase 1 are critical for apoptosis signal-regulating kinase 1-JNK/p38 activation.Li X et al
191838032009Modulation of the beta-catenin signaling pathway by the dishevelled-associated protein Hipk1.Louie SH et al
196469652009HIPK1 interacts with c-Myb and modulates its activity through phosphorylation.Matre V et al
219709552011Pax5: a master regulator of B cell development and leukemogenesis.Medvedovic J et al
190205462009Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia.Nebral K et al
230712922012Homeodomain-interacting protein kinase 1 (HIPK1) expression in breast cancer tissues.Park BW et al
236762192013HIPK1 drives p53 activation to limit colorectal cancer cell growth.Rey C et al
186061972008HIPKs: Jack of all trades in basic nuclear activities.Rinaldo C et al
235650592013Transcriptional corepressors HIPK1 and HIPK2 control angiogenesis via TGF-β-TAK1-dependent mechanism.Shang Y et al
129680342003Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization.Song JJ et al
166801442006Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes.Zhang Z et al


Fusion gene

PAX5/HIPK1 PAX5 (9p13.2) HIPK1 (1p13.2) M t(1;9)(p13;p12)|PAX5/HIPK1 PAX5 (9p13.2) HIPK1 (1p13.2) TIC


Jean-Loup Huret

t(1;9)(p13;p12) PAX5/HIPK1

Atlas Genet Cytogenet Oncol Haematol. 2014-02-01

Online version: http://atlasgeneticsoncology.org/haematological/1557/t(1;9)(p13;p12)