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WHO Classification of Tumours
Myeloid and lymphoid neoplasms with PDGFRA rearrangement
Tumours of haematopoietic and lymphoid tissues


Definition

The most common MPN associated with PDGFRA rearrangement is that associated with FIP1L1-PDGFRA formed as a result of a cryptic deletion at 4q12
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Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG (2003)
A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.
N Engl J Med 348: 1201-14



(Table 3.01). Presentation is generally as CEL but can be as AML, T-LBL or both simultaneously
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Metzgeroth G, Walz C, Score J, Siebert R, Schnittger S, Haferlach C, Popp H, Haferlach T, Erben P, Mix J, Müller MC, Beneke H, Müller L, Del Valle F, Aulitzky WE, Wittkowsky G, Schmitz N, Schulte C, Müller-Hermelink K, Hodges E, Whittaker SJ, Diecker F, Döhner H, Schuld P, Hehlmann R, Hochhaus A, Cross NC, Reiter A (2007)
Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma.
Leukemia 21: 1183-8



. Acute transformation can follow presentation as CEL. Organ damage occurs as a result of leukaemic infiltration or the release of cytokines, enzymes or other proteins by the eosinophils and possibly also by mast cells. The peri­pheral blood (PB) eosinophil count is markedly elevated (in cases reported to date it has almost always been ≥1.5x109/L) although it should be noted that, in some series of patients, investigation was confined to patients with eosinophilia. There is no Ph chromosome or BCR-ABL1 fusion gene. Except when there is transformation to acute leukaemia, there are <20% blasts in the PB and bone marrow (BM).

> Variants
A number of possible molecular variants of FIP1L1-PDGFRA-associated CEL have been recognized in which there are other fusion genes incorporating part of PDGFRA. A male patient with imatinib-­responsive CEL was found to have a KIF5B-PDGFRA fusion gene associated with a complex chromosomal abnormality involving chromosomes 3, 4 and 10

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Score J, Curtis C, Waghorn K, Stalder M, Jotterand M, Grand FH, Cross NC (2006)
Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia.
Leukemia 20: 827-32



, and a female patient had a CDK5RAP2-PDGFRA fusion gene associated with ins(9;4)(q33;q12q25)
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Walz C, Curtis C, Schnittger S, Schultheis B, Metzgeroth G, Schoch C, Lengfelder E, Erben P, Müller MC, Haferlach T, Hochhaus A, Hehlmann R, Cross NC, Reiter A (2006)
Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene.
Genes Chromosomes Cancer 45: 950-6



. A male patient with t(2;4)(p24;q12) and a STRN-PDGFRA fusion gene
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Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G, Minervini MM, Stewart J, Reiter A, Cross NC (2007)
Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia.
Br J Haematol 138: 77-81



and another with t(4;12)(q2?3;p1?2) and an ETV6-PDGFRA fusion gene, both with the haematological features of CEL, responded to low-dose imatinib
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Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G, Minervini MM, Stewart J, Reiter A, Cross NC (2007)
Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia.
Br J Haematol 138: 77-81



.

Patients with t(4;22)(q12;q11) and a BCR-PDGFRA fusion gene, four cases of which have been described, have disease characteristics intermediate between those of FIP1L1-PDGFRA-associated eosinophilic leukaemia and those of BCR-ABL1-positive chronic myelogeneous leukaemia; eosinophilia may or may not be prominent

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Baxter EJ, Hochhaus A, Bolufer P, Reiter A, Fernandez JM, Senent L, Cervera J, Moscardo F, Sanz MA, Cross NC (2002)
The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA.
Hum Mol Genet 11: 1391-7




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Gavrilescu LC, Cross NCP, Van Etten RA (2006)
Distinct leukemogenic activity and imatinib responsiveness of a BCR-PDGFRalpha fusion tyrosine kinase.
Blood 108: Abstract 3634.




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Safley AM, Sebastian S, Collins TS, Tirado CA, Stenzel TT, Gong JZ, Goodman BK (2004)
Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia.
Genes Chromosomes Cancer 40: 44-50




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Trempat P, Villalva C, Laurent G, Armstrong F, Delsol G, Dastugue N, Brousset P (2003)
Chronic myeloproliferative disorders with rearrangement of the platelet-derived growth factor alpha receptor: a new clinical target for STI571/Glivec.
Oncogene 22: 5702-6



. Accelerated phase
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Baxter EJ, Hochhaus A, Bolufer P, Reiter A, Fernandez JM, Senent L, Cervera J, Moscardo F, Sanz MA, Cross NC (2002)
The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA.
Hum Mol Genet 11: 1391-7



and T
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Baxter EJ, Hochhaus A, Bolufer P, Reiter A, Fernandez JM, Senent L, Cervera J, Moscardo F, Sanz MA, Cross NC (2002)
The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA.
Hum Mol Genet 11: 1391-7



and B lymphoblastic transformation
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Trempat P, Villalva C, Laurent G, Armstrong F, Delsol G, Dastugue N, Brousset P (2003)
Chronic myeloproliferative disorders with rearrangement of the platelet-derived growth factor alpha receptor: a new clinical target for STI571/Glivec.
Oncogene 22: 5702-6



have been reported. The condition is imatinib-sensitive
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Safley AM, Sebastian S, Collins TS, Tirado CA, Stenzel TT, Gong JZ, Goodman BK (2004)
Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia.
Genes Chromosomes Cancer 40: 44-50




Click to access Pubmed
Trempat P, Villalva C, Laurent G, Armstrong F, Delsol G, Dastugue N, Brousset P (2003)
Chronic myeloproliferative disorders with rearrangement of the platelet-derived growth factor alpha receptor: a new clinical target for STI571/Glivec.
Oncogene 22: 5702-6



.

> Related Topics
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1
Chronic eosinophilic leukaemia, NOS
Systemic mastocytosis
Introduction: Myeloid Neoplasms