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(Paper co-edited with the European LeukemiaNet)
A new case of t(4;12)(q12;p13) in a secondary acute myeloid leukemia with review of literature
Written2011-03Sarah M Heaton, Frederick Koppitch, Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI, USA
Age and sex : 57 year(s) old male patient.
Previous History : no preleukemia
Hodgkin's Lymphoma, stage IVA at age 25 year, treated with ABVD for 12 months. Tumor mass in the upper cervical spine diagnosed at age 27 year, treated with laminectomy and five doses of radiation.
no inborn condition of note
Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; no central nervous system involvement
WBC : 0.8 x 109/L ; Hb : 9.7 g/dL ; platelets : 21.0 x 109/L; blasts : 18 % .
Bone marrow : Variably cellular with 20% myeloblasts and dysplastic changes in the erythroid and myeloid cell lines.
Cyto pathology classification
Cytology : His bone marrow showed 60% blasts, and dysplastic changes were noted in the erythroid and myeloid cell lines.
Immunophenotype : Flow cytometry (FCM) revealed that the blasts were of myeloid lineage expressing CD13, CD33, CD34, CD117, HLA-DR, and CD56.
Precise diagnosis : Acute myeloid leukemia (AML) with dysplastic changes.
Date of diagnosis: 08-2007
Treatment : He was treated with Idarubicin+Ara-c (3+7) regimen. Because of 15% residual blasts in bone marrow, patient received additional 2+5 therapy, and then he underwent consolidation with Ara-C. Result of karyotype: 46,XY[20]. On April 2008, the patient received a matched unrelated female donor stem cell transplant (SCT). 30 days post transplant; bone marrow revealed no morphological evidence of leukemia and the karyotype was 46,XX[20]. On June 2008; patient developed pancytopenia; WBC: 2.2 x 109/l; Hb: 11.6 g/dl; platelets: 18.0 x 103/l. His bone marrow showed an increased dysplastic changes and <5% blasts, suggestive of possible early relapse. The karyotype became abnormal (see below). On June 2010; bone marrow was hypocellular with 20% blasts and dysplastic changes in the erythroid and myeloid lineages. FCM revealed myeloblasts expressing CD4, CD7, CD33, CD34, CD56, CD117 and HLA-DR. myeloperoxidase was negative. Non-specific esterase was positive in occasional blasts. Cytology: AML possibly of monocytic origin (AML-M5).
Complete remission was obtained
Treatment related death : -
Relapse : +
Phenotype at relapse : M5-AML
Status : Alive 06-2010
Survival : 24 month(s)
Sample : Bone marrow ; culture time : 24 h, and 48h with 10% conditioned medium ; banding : GTG
Results : 46,XY,t(4;12)(q12;p13)[6]/46,XX[14] in June 2008 (post transplant)
Karyotype at relapse : 46,XY,t(4;12)(q12;p13)[12]/ 46,idem,del(7)(q22q36)[4]/ 47,idem,+19[2]/ 46,XX[2], consistent with the recurrence and clonal evolution of the leukemic clone.
Other molecular cytogenetics technics : Fluorescence in situ hybridization (FISH) using LSI 4q12 tricolor and LSI ETV6/RUNX1 ES dual color DNA probes were performed (Abbott Molecular. Downers Grove, IL) on the abnormal metaphase cells.
Other molecular cytogenetics results : Translocation of the PDGFRA gene in Toto, spectrunAqua (SA), to derivative 12 and colocalized with centromeric region of ETV6; Break within ETV6 gene locus, sepctrunGreen (SG) and the telomeric region of ETV6 translocated to derivative 4 (Figure 2 A-C).
Figure 1. G-banded karyotype showing the balanced t(4;12)(q12;p13) translocation.
Figure 2. FISH on abnormal metaphases; (A) Metaphase hybridized with LSI 4q12 tricolor DNA probe showed a translocation of PDGFRA (SA) to derivative chromosome 12 (arrow), with the dual fusion of spectrunOrange (SO) and spectrunGreen (SG) remained on derivative 4. (B) Metaphase hybridized with LSI ETV6/RUNX1 ES dual color probe revealed a split of ETV6 (SG) with the smaller signal being translcated to derivative 4 (arrows). (C) Metaphase hybridized with both LSI 4q12 and ETV6/RUNX1 probes showed PDGFRA (SA) translocted to derivative 12 adjacent to ETV6 locus (arrows).
Acute leukemia with t(4;12)(q11-q12;p13) is a rare, nonrandom event with an estimated incidence of 0.6% among adults according to Harada et al. (Harada et al., 1997). This translocation is seen mostly in adult AML but less frequent in pediatric ALL (Hamaguchi et al., 1999). A review of the literature revealed at least twenty-two additional cases with a t(4;12)(q11-q12;p13); eighteen adults and four children. The male to female ratio is 1.5:1 (1.7:1 in adults and 1:1 in children). The majority of patients are adults, aged 18 to 82 with the mean being 58.9 years old (Harada et al., 1995; Harada et al., 1997; Ma et al., 1997; Cools et al., 1999; Hamaguchi et al., 1999; Chaufaille et al., 2003; Manabe et al., 2010). Four children have been reported, aged 3-14 years old, of which three had ALL and the oldest had AML (Harada et al., 1997).
Among the 23 cases including our case with t(4;12) leukemia; 19 had AML; 3 ALL, and one unclassified leukemia. Common features to t(4;12) AML include dysplasia of three hematopoietic lineages (erythroid, myeloid and megakaryocytic), low or absent myeloperoxidase activity, basophilia and a pseudo-lymphoid morphology. The surface markers of the blasts show positivity for CD7, CD13, CD33, CD34 and HLA DR, suggesting that the leukemic cells have an immature myeloid stem cell origin (Harada et al., 1995; Ma et al., 1997; Hamaguchi et al., 1999). Of the reported t(4;12) AML cases; seven were characterized as AML-M0 and four AML-M1. Previous reports suggest that less than 50% of cases achieve remission with intensive induction chemotherapy. Of the patients who do not achieve morphologic remission, none survived beyond six months (Hamaguchi et al., 1999; Chaufaille et al., 2003; Manabe et al., 2010).
The breakpoint at 12p13 in t(4;12) AML is located within or near the ETV6 gene locus. The ETV6 gene has been implicated in both myeloid and lymphoid malignancies (Wlodarska et al., 1998). ETV6 belongs to the ETS family of transcription factors and has two important domains: HLH and an ETS DNA binding domain. Cools et al, found the t(4;12) caused the ETV6 gene recombined to CHIC2 (formerly BLT) (Cools et al., 1999). A number of genes have been mapped to the band 4q12 including mac25, PDGFRA, AFP, and a beta-sarcoglycan gene (Hamaguchi et al., 1999).
The case reported here shared some features to those reported in the literature including positivity for CD7, CD33, CD34, CD117 and HLA-DR, lack of myeloperoxidase activity and dysplastic bone marrow. Unlike other reported cases, bone marrow basophilia and high platelets were not found. Clearly in our case, FISH showed a break within ETV6/12p13 gene, and colocalization of PDGFR1 gene to derivative 12 next to 5' ETV6 region.
Internal links
Atlas Cardt(4;12)(q11-q21;p13)
Case ReportThe rare t(4;12)(q11;p13) in an elderly patient with de novo AML with multilineage dysplasia co-expressing stem cell markers
Case Reportt(4;12)(q11;p13) in an acute myeloid leukemia without maturation with myelodysplasia
Case ReportA t(4;12)(q11;p13) in a patient with coincident CLL at the same time of AML diagnosis
A specific chromosome abnormality of t(4;12)(q11-12;p13) in CD7+ acute leukaemia.
Harada H, Asou H, Kyo T, Asaoku H, Iwato K, Dohy H, Oda K, Harada Y, Kita K, Kamada N.
Br J Haematol. 1995 Aug;90(4):850-4.
PMID 7545425
Characterization of acute leukemia with t(4;12).
Harada H, Harada Y, Eguchi M, Dohy H, Kamada N.
Leuk Lymphoma. 1997 Mar;25(1-2):47-53.
PMID 9130613
CD7+ acute myeloid leukaemia with 'mature lymphoid' blast morphology, marrow basophilia and t(4;12)(q12;p13).
Ma SK, Lie AK, Au WY, Wan TS, Chan LC.
Br J Haematol. 1997 Dec;99(4):978-80.
PMID 9432054
Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies.
Wlodarska I, La Starza R, Baens M, Dierlamm J, Uyttebroeck A, Selleslag D, Francine A, Mecucci C, Hagemeijer A, Van den Berghe H, Marynen P.
Blood. 1998 Feb 15;91(4):1399-406.
PMID 9454771
Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13).
Cools J, Bilhou-Nabera C, Wlodarska I, Cabrol C, Talmant P, Bernard P, Hagemeijer A, Marynen P.
Blood. 1999 Sep 1;94(5):1820-4.
PMID 10477709
A new translocation, t(2;4;12)(p21;q12;p13), in CD7-positive acute myeloid leukemia: a variant form of t(4;12).
Hamaguchi H, Nagata K, Yamamoto K, Kobayashi M, Takashima T, Taniwaki M.
Cancer Genet Cytogenet. 1999 Oct 15;114(2):96-9.
PMID 10549263
t(4;12)(q11;p13): a rare chromosomal translocation in acute myeloid leukemia.
Chauffaille Mde L, Fermino FA, Pelloso LA, Silva MR, Bordin JO, Yamamoto M.
Leuk Res. 2003 Apr;27(4):363-6. (REVIEW)
PMID 12531229
A rare t(4;12)(q12;p13) in an adolescent patient with acute myeloid leukemia.
Manabe M, Nakamura K, Inaba A, Fujitani Y, Kosaka S, Yamamura R, Inoue A, Hino M, Senzaki H, Ohta K.
Cancer Genet Cytogenet. 2010 Jul 1;200(1):70-2.
PMID 20513538


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