t(1;5)(q21;q32) PDE4DIP/PDGFRB

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

t(1;5)(q21-23;q31-33)

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.

Keywords

PDGFRB; PDE4DIP; TPM3; eosinophilia; myeloproliferative disorder; PDE4DIP/PDGFRB; TPM3/PDGFRB

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo	C420,C421,C424
ICD-Morpho	9945/3 Chronic myelomonocytic leukaemia
ICD-Morpho	9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
ICD-Morpho	9964/3 Chronic eosinophilic leukaemia, NOS
ICD-Morpho	9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho	9983/3 Refractory anaemia with excess blasts
ICD-Morpho	9946/3 Juvenile myelomonocytic leukaemia
ICD-Morpho	9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho	9673/3 Mantle cell lymphoma
ICD-Morpho	9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS; Primary DLBCL of the CNS; Primary cutaneous DLBCL, leg type; EBV positive DLBCL of the elderly; DLBCL associated with chronic inflammation; B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
Atlas_Id	1115
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.
	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.

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 / cell stem 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). Ref Genes Sex/age Disease Karyotype Survival 1 PDE4DIP/PDGFRB F/0 MPD 46,XX,t(1;5)(q23;q33) 19+ months, on imatinib 2 TPM3/PDGFRB M/21 CES 46,XY,t(1;5)(q21;q33) Therapy with  interferon and imatinib, alive 10+ years 3 TPM3/PDGFRB M/8 CEL t(1;5)(q21;q33) JMML from 1 year old; complete remission on imatinib, alive 8+ years? 4 PDGFRB rearranged M aCML/CEL t(1;5)(q21;q33)   5 PDGFRB rearranged M MPD t(1;5)(q22;q31)   6 PDGFRB rearranged M/0 JMML t(1;5)(q21;q33) 16+ months, on imatinib 7 No PDGFRB rearrangement M MDS/AML t(1;5)(q21;q31)   8 ? F/31 CML 46,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/0 JMML 46,XX,t(1;5)(q21;q33) Alive after BMT 10+ years 10 ? M AML 46,XY,t(8;21)(q22;q22) --> 46,XY,t(1;5)(q21;q33),t(8;21)/46,idem,del(11)(p13)   11 ? M/70 AML 45,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/51 B-ALL 46,XY,t(1;5)(q21;q31),del(9)(p12)   13 ? F/22 B-ALL 46,XX,t(1;5)(q21;q32)/42-48,idem,+8/48,idem,+der(5)t(1;5),+21   14 ? F/67 DLBCL  (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/0 MPD 46,XX,t(1;5)(q23;q33) died 9 month after diagnosis 16 ? M/0 MPD 46,XY,t(1;5)(q23;q33) Alive 14+ months 17 ? M/21 CEL 46,XY,t(1;5)(q23;q31) interferon therapy, alive 7+ years 18 ? F/79 RAEB 44,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/13 B-ALL 46,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.

Cytogenetics

Additional anomalies

Sole anomaly in 12 out of 19 described patients, found in association with t(9;22)(q34;q11) in a sideline in CML (Hild & Fonatsch.,1990), t(8;21)(q22;q22) in AML (Kern et al., 2002), del(9)(p12) in ALL (Coyaud et al., 2010), inv(3)(q21q26)/ -7 in AML (Shearer et al., 2010) and complex karyotypes in 3 patients (Le Baccon et al., 2001; Xu et al., 2010; Safavi et al., 2015).

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	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	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	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

Hybrid geneHybrid gene

Description	PDE4DIP/PDGFRB. 5' PDE4DIP - 3' PDGFRB; PDE4DIP (KIAA0477 isoform) fuses in frame PDGFRB exon 11. The reciprocal PDGFRB-PDE4DIP is not expressed.
Description	TPM3/PDGFRB. TPM3 fused exon 7 with exon 11 of the PDGFRB

Fusion Protein

Description	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.

To be noted

Additional cases are needed to delineate the epidemiology of these rare entities (i.e. t(1;5)(q21;q32) PDE4DIP/PDGFRB and t(1;5)(q21-23;q32) TPM3/PDGFRB) you are welcome to submit a paper to our new Case Report section.

Bibliography

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Citation

This paper should be referenced as such :

Zamecnikova A

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. in press

On line version : http://AtlasGeneticsOncology.org/Anomalies/t0105q22q33ID1115.html

History of this paper:

Huret, JL. t(1;5)(q22;q33). Atlas Genet Cytogenet Oncol Haematol. 2006;10(4):257-258.

http://documents.irevues.inist.fr/bitstream/handle/2042/38354/04-2006-t0105q22q33ID1115.pdf

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes

PDE4DIP

PDGFRB

Translocations implicated (Data extracted from papers in the Atlas)

	t(1;5)(q22;q33) PDE4DIP/PDGFRB
	t(1;5)(q22;q33) TPM3/PDGFRB

External links

Mitelman database	t(1;5)(q22;q33) [Case List]    t(1;5)(q22;q33) [Transloc-MCList] PDE4DIP/PDGFRB [Fusion-MCList]
Mitelman database	t(1;5)(q22;q33) [Case List]    t(1;5)(q22;q33) [Transloc-MCList] TPM3/PDGFRB [Fusion-MCList]
arrayMap (UZH-SIB Zurich)	Morph ( 9945/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9975/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9964/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9983/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9946/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9811/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9673/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)	Morph ( 9680/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]

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