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t(4;22)(q12;q11) BCR::PDGFRA

Written2004-09Barbara K Goodman, Anne Michele Safely
Clinical Cytogenetics, Molecular Diagnostics Laboratories, Duke University Health System, Box 3631, Durham, NC 27710, UK

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ICD-Morpho 9965/3 Myeloid and lymphoid neoplasms with PDGFRA rearrangement
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Atlas_Id 1153
  Partial karyotype showing chromosomes 4 and 22.

Clinics and Pathology

Disease Reported in 3 cases; myeloproliferative disorder : atypical chronic myeloid leukemia (aCML) (Philadelphia chromosome-negative) .
Etiology One case was post-treatment for lymphoma, thus suspected to be a secondary MPD.
Clinics 3 cases shared characteristics of splenic enlargement, eosinophilia and male predominance.
Peripheral blood smear showing anemia, leukocytosis with increased granulocytes and precursors, and eosinophilia. Bone marrow showing hypercellularity with marked myeloid hyperplasia, mild eosinophilia, no increase in blasts.
Prognosis One patient on treatment with good response to imatinib mesylate.


Note t(4;22)(q12;q11.2), easily distinguished cytogenetically.
Cytogenetics Molecular FISH for BCR- ABL1 is negative for fusion but will show extra signal for BCR when using the dual fusion probe set. BCR-ABL1 PCR is negative.
  Interphase FISH showing 3 signals for BCR (green), suggesting rearrangement. Two normal signals for ABL1 (red).
Additional anomalies The t(4;22) was observed as the sole anomaly in the few reported cases to date.

Genes involved and Proteins

Gene NamePDGFRA (platelet-derived growth factor receptor, alpha polypeptide)
Location 4q12
Note Member of the protein-tyrosine kinase receptor family subclass III that includes the colony stimulating factor-1, c-KIT, FLT1, and FLT3/FLK2. Suggested role for normal PDGFRA receptor expression during periods of glial cell development and connective tissue growth.
Dna / Rna 23 exons; includes 2 intracellular tyrosine kinase domains, TK1 and TK2 (exons 13-15 and 17-21), 5 extracellular Ig-like domains (exons 3-10), and a hydrophobic transmembrane domain (exon 10). The cytoplasmic region also encodes an ATP binding site.
Protein 170-kD transmembrane glycoprotein that normally binds all PDGF isoforms, AA, AB, and BB at its extracellular Ig domain.
Gene NameBCR (Breakpoint cluster region)
Location 22q11.23
Dna / Rna 23 exons; alternate splicing.
Protein 160-kDa protein; contains a unique serine/threonine kinase activity and at least two SH2 binding sites encoded in its first exon and a C-terminal domain that functions as a GTPase activating protein for p21(rac).

Result of the chromosomal anomaly

Hybrid gene
Note 5'BCR-3'PDGFRA fusion
Description Fusion of BCR exon 7, 12 or 17 (in 3 cases described) with PDGFRA exon 12, in frame, containing intronic sequence from BCR in two cases.
Fusion Protein
Description 169 kDa protein in one case, somewhat smaller in two others.
Expression Localisation Predicted to be localized intracellularly
Oncogenesis Alteration of tyrosine kinase activity secondary to loss of regulatory and PDGF binding domains; also, BCR domains may significantly affect BCR-PDGFRA downstream signaling pathways as seen with BCR-ABL fusion.


The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA.
Baxter EJ, Hochhaus A, Bolufer P, Reiter A, Fernandez JM, Senent L, Cervera J, Moscardo F, Sanz MA, Cross NC
Human molecular genetics. 2002 ; 11 (12) : 1391-1397.
PMID 12023981
Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders.
Baxter EJ, Kulkarni S, Vizmanos JL, Jaju R, Martinelli G, Testoni N, Hughes G, Salamanchuk Z, Calasanz MJ, Lahortiga I, Pocock CF, Dang R, Fidler C, Wainscoat JS, Boultwood J, Cross NC
British journal of haematology. 2003 ; 120 (2) : 251-256.
PMID 12542482
CML after treatment for lymphoid malignancy: Therapy-related CML or coincidence?
Bolañ J, Sarkodee-Adoo C, Khanwani SL
American journal of hematology. 2002 ; 71 (2) : page 139.
PMID 12353319
Identification and structural analysis of the A type receptor for platelet-derived growth factor. Similarities with the B type receptor.
Claesson-Welsh L, Hammacher A, Westermark B, Heldin CH, Nistér M
The Journal of biological chemistry. 1989 ; 264 (3) : 1742-1747.
PMID 2536372
PDGFRA activating mutations in gastrointestinal stromal tumors.
Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA
Science (New York, N.Y.). 2003 ; 299 (5607) : 708-710.
PMID 12522257
Structure, organization, and transcription units of the human alpha-platelet-derived growth factor receptor gene, PDGFRA.
Kawagishi J, Kumabe T, Yoshimoto T, Yamamoto T
Genomics. 1995 ; 30 (2) : 224-232.
PMID 8586421
Functional importance of platelet-derived growth factor (PDGF) receptor extracellular immunoglobulin-like domains. Identification of PDGF binding site and neutralizing monoclonal antibodies.
Lokker NA, O'Hare JP, Barsoumian A, Tomlinson JE, Ramakrishnan V, Fretto LJ, Giese NA
The Journal of biological chemistry. 1997 ; 272 (52) : 33037-33044.
PMID 9407086
A FISH study of variant Philadelphia rearrangements.
Reddy KS, Sulcova V
Cancer genetics and cytogenetics. 2000 ; 118 (2) : 121-131.
PMID 10748292
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.
Safley AM, Sebastian S, Collins TS, Tirado CA, Stenzel TT, Gong JZ, Goodman BK
Genes, chromosomes & cancer. 2004 ; 40 (1) : 44-50.
PMID 15034867
Chronic myeloproliferative disorders with rearrangement of the platelet-derived growth factor alpha receptor: a new clinical target for STI571/Glivec.
Trempat P, Villalva C, Laurent G, Armstrong F, Delsol G, Dastugue N, Brousset P
Oncogene. 2003 ; 22 (36) : 5702-5706.
PMID 12944919


This paper should be referenced as such :
Goodman, BK ; Safely, AM
Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):319-321.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]


Translocations implicated (Data extracted from papers in the Atlas)

 t(4;22)(q12;q11) BCR/PDGFRA

External links

BCR (22q11.23) PDGFRA (4q12)

BCR (22q11.23) PDGFRA (4q12)

Mitelman databaset(4;22)(q12;q11)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9965/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9975/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
Mitelman databaseBCR::PDGFRA [MCList]  BCR (22q11.23) PDGFRA (4q12)
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
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