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.

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).

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.

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.

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.

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.

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.

PDE4DIP/PDGFRB

TPM3/PDGFRB

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.