t(1;5)(q21;q32) PDE4DIP/PDGFRB
t(1;5)(q21-23;q32) TPM3/PDGFRB
t(1;5)(q21-23;q31-33)

2018-07-01   Adriana Zamecnikova 

1.Kuwait Cancer Control Center, Kuwait annaadria@yahoo.com
2.Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France

Abstract

Chromosomal translocations involving chromosome bands 5q31-33 that contain the gene encoding the platelet-derived growth factor beta receptor (PDGFRB) are associated with a significant minority of patients with BCR/ABL1-negative chronic myeloid neoplasms. To date, numerous PDGFRB fusion partners have been identified, with the vast majority being reported only in sporadic cases. Although PDGFRB fusions are rare, their identification is important in order to identify patients in whom targeted therapy with tyrosine kinase inhibitors is likely to be successful.

Clinics and Pathology

Disease

Myeloproliferative disorders (MPD) with eosinophilia (or chronic eosinophilic leukemia (CEL) and sporadic cases with acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (ALL) or lymphoma.

Phenotype stem cell origin

Phenotypically diverse myeloid neoplasms that include patients that have been categorized as: chronic eosinophilic leukemia (CEL)/ atypical chronic myeloid leukemia with eosinophilia in 4 (Luciano et al., 1999; Rosati et al., 2006, Baxter et al., 2003, Li et al., 2011), chronic myeloproliferative disorder (MPD) in 2 (Darbyshire et al., 1987; Baxter et al., 2003), juvenile myelomonocytic leukemia (JMML) in 2, 1 of them congenital JMML (Grainger et al., 2002 Abraham et al., 2010), chronic myeloid leukemia (CML) in 1 (Hild & Fonatsch.,1990), myelodysplastic/myeloproliferative disease in 1 (Wilkinson et al., 2003), refractory anemia with excess of blasts in 1 (RAEB) (Xu et al., 2010) and acute myeloid leukemia in 3 (Baxter et al., 2003; Kern et al., 2002; Shearer et al., 2010). The remaining cases were lymphoid malignancies: 5 B-cell ALL (Craig et al., 1990; Barriga et al., 1996; Coyaud et al., 2010; Safavi et al., 2015), 1 mantle cell lymphoma (MCL) (Le Baccon et al., 2001) and 1 diffuse large B-cell lymphoma (DLBCL) (Le Baccon et al., 2001).

Epidemiology

Male prevalence (12 males and 7 females) aged 0 to 79 years (median age 21 years) and notably, 5 patients were infants (1 male and 3 females) (Darbyshire et al., 1987; Wilkinson et al., 2003; Grainger et al., 2002; Abraham et al., 2010) (Table 1). Because the phenotypes are different, it may be that genes involved in this/these disease(s) are not similar; PDE4DIP and PDFRGB were found involved in MPD with eosinophilia (see below).
RefGenesSex/ageDiseaseKaryotypeSurvival
1PDE4DIP/PDGFRBF/0MPD46,XX,t(1;5)(q23;q33)19+ months, on imatinib
2TPM3/PDGFRBM/21CES46,XY,t(1;5)(q21;q33)Therapy with  interferon and imatinib, alive 10+ years
3TPM3/PDGFRBM/8CELt(1;5)(q21;q33)JMML from 1 year old; complete remission on imatinib, alive 8+ years?
4PDGFRB rearrangedMaCML/CELt(1;5)(q21;q33) 
5PDGFRB rearrangedMMPDt(1;5)(q22;q31) 
6PDGFRB rearrangedM/0JMMLt(1;5)(q21;q33)16+ months, on imatinib
7No PDGFRB rearrangementMMDS/AMLt(1;5)(q21;q31) 
8?F/31CML46,XX,add(1)(q?),t(9;22)(q34;q11) --> 46,XX,dup(1)(q23q32),t(9;22)/46,XX,t(1;5)(q21-22;q31),t(9;22) 
9?F/0JMML46,XX,t(1;5)(q21;q33)Alive after BMT 10+ years
10?MAML46,XY,t(8;21)(q22;q22) --> 46,XY,t(1;5)(q21;q33),t(8;21)/46,idem,del(11)(p13) 
11?M/70AML45,XY,-7/46,idem,+21) --> 46-47,XY,inv(3)(q21q26),-7,+21,+mar/45,XY,inv(3),-7/45,XY,t(1;5)(q21;q31),inv(3),-7 RPN1/MECOM 
12?M/51B-ALL46,XY,t(1;5)(q21;q31),del(9)(p12) 
13?F/22B-ALL46,XX,t(1;5)(q21;q32)/42-48,idem,+8/48,idem,+der(5)t(1;5),+21 
14?F/67DLBCL  (LN)51,XX,add(1)(p12),t(1;5)(q21;q31),der(2)dup(2)(p16p25)t(1;2) (q21;q31),der(3)t(1;3)(p21;q22),der(4)t(4;11)(q35;q13),del(6)(p21),+del(7)(?q22?q34),del(8)(q24),add(11)(p12),+12,+21,+2mar 
15?F/0MPD46,XX,t(1;5)(q23;q33)died 9 month after diagnosis
16?M/0MPD46,XY,t(1;5)(q23;q33)Alive 14+ months
17?M/21CEL46,XY,t(1;5)(q23;q31)interferon therapy, alive 7+ years
18?F/79RAEB44,XX,t(1;5)(q23;q33),-7,der(12)t(7;12)(q?;p?)t(7;19)(q?;?),-18,der(19)t(11;19)(?;p11) 
19?M/13B-ALL46,XY,t(1;5)(q23;q33)Relapse after 3 months; CNS relapse on day + 106 after BMT and died.

Abbreviations: M, male; F, female; MPD, Myeloproliferative disorder; CES; Chronic eosinophilic syndrome; CEL; Chronic eosinophilic leukemia; aCML, Atypical chronic myeloid leukemia; JMML, Juvenile myelomonocytic leukemia; MDS, myelodyslastic syndrome; AML; Acute myeloid leukemia; CML, Chronic myeloid leukemia; BMT, bone marrow transplantation; B-ALL, B-cell Acute lymphoblastic leukemia; DLBCL, Diffuse large B-cell lymphoma; LN, lymph node;, RAEB, Refractory anemia with excess of blasts.
1. Wilkinson et al., 2003; 2. Rosati et al., 2006; 3. Li et al., 2011; 4-5,7. Baxter et al., 2003; 6. Abraham et al., 2010; 8. Hild & Fonatsch.,1990; 9. Grainger et al., 2002; 10. Kern et al., 2002; 11. Shearer et al., 2010; 12. Coyaud et al., 2010; 13. Safavi et al., 2015;14. Le Baccon et al., 2001; 15-16. Darbyshire et al., 1987; 17. Luciano et al., 1999; 18. Xu et al., 2010; 19. Barriga et al., 1996.

Clinics

Patients typically present with myeloproliferative neoplasm with eosinophilia and a spectrum of morphologic presentations. Although eosinophilia is characteristic of myeloid neoplasms associated with PDGFRB rearrangement, marked eosinophilia is not an invariable feature and the clinical presentation is variable. Patients are typically male and while children are rarely affected with PDGFRB gene fusions, 6 out of 19 described patients with t(1;5)(q21-23;q31-33) were children aged 0 to 13 years.

Prognosis

One of the infants with MPD died 9 month after diagnosis and the other remains well on therapy 14 months from diagnosis (Darbyshire et al., 1987). The infant with PDE4DIP/PDGFRB fusion had refractory and progressive disease, but after therapy with imatinib was started complete clinical and hematologic remission, as well as major cytogenetic response was achieved (Wilkinson et al., 2003). 1 infant with JMML received autologous stem cell transplantation after initial cytoreductive therapy failed to control the disease and is alive at 10 years in full cytogenetic remission (Grainger et al., 2002) and 1 with congenital JMML is alive 16+ months on imatinib therapy (Abraham et al., 2010). The 8-year-old male with CEL and TPM3/PDGFRB fusion had rapid hematologic response and reduction of TPM3/PDGFRB transcripts after targeted therapy with imatinib (Li et al., 2011). The 21-years old patient with CEL obtained complete hematologic and major cytogenetic response after two years of interferon therapy and is alive 7 years from diagnosis (Luciano et al., 1999). The other 21- years old male with CEL and confirmed TPM3/PDGFRB fusion received interferon therapy for 10 years resulting in major cytogenetic response and after continuing with imatinib he achieved hematological, cytogenetic and FISH remission (Rosati et al., 2006). The 13-years-old boy with high-risk early pre-B ALL underwent allogeneic bone marrow transplantation after relapse but after a short second remission he had a central nervous system relapse and died (Barriga et al., 1996). From these data, it appears that patients with t(1;5)(q21-23;q31-33) and PDGFRB rearrangement have imatinib-responsive disease with durable remissions.

Genes Involved and Proteins

Note
Involvement of PDGFRB was demonstrated in several patients with t(1;5)(q21-23;q31-33) and there has been two identified PDGFRB partner genes located at 1q21, PDE4DIP (Wilkinson et al., 2003) and TPM3 (Rosati et al., 2006; Li et al., 2011). It is also possible that other genes from the 5q31-q33 region such as TCOF1, CSF1R and CDX1 are potential translocation targets as well as IL3, IL5 and CSF2 (GM-CSF) (cytokines involved in eosinophilopoiesis) may be dysregulated in the translocation process, at least in some patients.
Gene name
PDE4DIP (phosphodiesterase 4D interacting protein (myomegalin))
Location
1q21.1
Protein description
PDE4DIP codes for a protein called myomegalin; interacts with the cyclic nucleotide phosphodiesterase PDE4D; there are at least 2 major isoforms of myomegalin in humans (KIAA0454 and KIAA0477), encoding N and C termini (Verde et al., 2001; Wilkinson et al., 2003); myomegalin encodes several putative oligomerization domains capable of activating PDGFRB. They include a leucine zipper (LZ) domain and several coiled-coil structures.
Gene name
TPM3 (Tropomyosin 3 Tropomyosins TropomyosinsTropomyosinsTropomyosins)
Location
1q21.3
Protein description
Member of the tropomyosin family of actin-binding proteins that are dimers of coiled coil proteins; binds and to actin filaments in muscle and non-muscle cells; mediates myosin-actin response to calcium ions in skeletal muscles and regulates the access to other actin-binding proteins; non-muscle isoform is found in cytoskeletal microfilaments (Rosati et al., 2006).
Gene name
PDGFRB (platelet-derived growth factor receptor, beta polypeptide)
Location
5q32
Protein description
PDGFRB is the receptor for PDGFB (platelet-derived growth factor-b); Ig like, transmembrane and tyrosine kinase domains; membrane tyrosine kinase; can homodimerize; activated in response to ligand binding and receptor dimerization.

Result of the Chromosomal Anomaly

Description

PDE4DIP/PDGFRB. 5 PDE4DIP - 3 PDGFRB; PDE4DIP (KIAA0477 isoform) fuses in frame PDGFRB exon 11. The reciprocal PDGFRB-PDE4DIP is not expressed.TPM3/PDGFRB. TPM3 fused exon 7 with exon 11 of the PDGFRB. A reciprocal fusion of exon 10 of PDGFRB to exon 8 has been detected (Rosati et al., 2006).The first 905 amino acids of PDE4DIP, including the coiled-coil domains are fused to the transmembrane and the tyrosine kinase domains of PDGFRB.

Oncogenesis

Hematolymphoid neoplasms associated with PDGFRB gene fusions are infrequent and can be observed in a wide range of hematological malignancies including myeloproliferative neoplasms with eosinophilia, atypical CML, Ph-like acute lymphoblastic leukemia and AML. Genetically they are equally heterogeneous with at least 30 fusion genes having been described, resulting from the formation of abnormal fusion genes that encode constitutively activated tyrosine kinases. While several PDGFRB partner genes remain to be characterized, constitutive activation of protein tyrosine kinases is a common feature of neoplasms with fusion genes derived from PDGFRB, triggering downstream signaling, but importantly they can be successfully targeted by tyrosine kinase inhibitors such as imatinib.

Bibliography

Pubmed IDLast YearTitleAuthors
86467391996t(1;5)(q23;q33) in a patient with high-risk B-lineage acute lymphoblastic leukemia.Barriga F et al
201601642010Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study.Coyaud E et al
36635041987A myeloproliferative disease in two infants associated with eosinophilia and chromosome t(1;5) translocation.Darbyshire PJ et al
119725352002Cultured autografting for juvenile myelomonocytic leukaemia.Grainger JD et al
23576951990Cytogenetic peculiarities in chronic myelogenous leukemia.Hild F et al
123573612002Karyotype instability between diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy.Kern W et al
115794652001Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma.Le Baccon P et al
210728212011Molecular diagnosis and targeted therapy of a pediatric chronic eosinophilic leukemia patient carrying TPM3-PDGFRB fusion.Li Z et al
104069091999AlphaIFN-induced hematologic and cytogenetic remission in chronic eosinophilic leukemia with t(1;5).Luciano L et al
168380282006TPM3/PDGFRB fusion transcript and its reciprocal in chronic eosinophilic leukemia.Rosati R et al
252610972015Novel gene targets detected by genomic profiling in a consecutive series of 126 adults with acute lymphoblastic leukemia.Safavi S et al
205568212010Development of a dual-color, double fusion FISH assay to detect RPN1/EVI1 gene fusion associated with inv(3), t(3;3), and ins(3;3) in patients with myelodysplasia and acute myeloid leukemia.Shearer BM et al
111340062001Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase.Verde I et al
129074572003Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib.Wilkinson K et al
200890002010Multiplex fluorescence in situ hybridization in identifying chromosome involvement of complex karyotypes in de novo myelodysplastic syndromes and acute myeloid leukemia.Xu W et al

Summary

Fusion gene

PDE4DIP/PDGFRB , TPM3/PDGFRB

Note

Included are reported patients with reciprocal 5q31-5q33 translocations, with or without PDGFRB involvement as patients with rearrangements of this gene had translocations that appeared cytogenetically to involve bands from 5q31 to 5q33. Therefore, in patients with reciprocal translocation involving chromosome band 5q31-33 it is important to identify involvement of PDGFRB by molecular testing or by the use of dual color break-apart probes that allows detection of PDGFRB rearrangements before considering targeted therapy.
Atlas Image
Figure 1. Partial karyotypes with t(1;5)(q25;q33) (A). Fluorescence in situ hybridization with LSI 1p36/1q25 dual color probe (Vysis. Abott Molecular, US) showing the signal for 1q25 on der(1) chromosome (green signal) indicative of breakpoint distal to the probe (B). Hybridization with LSI 1p36/1q25 dual color and Kreatechô PDGFRB Break (Leica Biosystems, US) probes revealed PDGFRB remains on der(5) and is not disrupted by the translocation (C) - Courtesy Adriana Zamecnikova.

Citation

Adriana Zamecnikova

t(1;5)(q21;q32) PDE4DIP/PDGFRB
t(1;5)(q21-23;q32) TPM3/PDGFRB
t(1;5)(q21-23;q31-33)

Atlas Genet Cytogenet Oncol Haematol. 2018-07-01

Online version: http://atlasgeneticsoncology.org/haematological/1115/t(1;5)(q21-23;q32)

Historical Card

2006-04-01 t(1;5)(q21;q32) PDE4DIP/PDGFRB
t(1;5)(q21-23;q32) TPM3/PDGFRB
t(1;5)(q21-23;q31-33)
 by  Jean-Loup Huret 

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

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