Case Reports t1213p13q12PerryID100095

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(Paper co-edited with the European LeukemiaNet)
Acute myeloid leukemia with t(12;13)(p13;q12) and ETV6 involvement; Case report and review of literature
Written2018-04William R. Perry, Deborah Schloff, Anwar N. Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI, USA;
Age and sex : 61 year(s) old male patient.
Previous History : no preleukemia
no previous malignant disease
no inborn condition of note
Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; no central nervous system involvement
WBC : 5.4 x 109/L ; Hb : 6.8 g/dL ; platelets : 56 x 109/L; blasts : 22 % (myeloblasts).
Bone marrow : 60% cellularity; 30% intermediate-to-large size blasts with open chromatin and no Auer rods; decreased trilineage hematopoiesis; significant dysplasia of erythroid elements.
Cyto pathology classification
Phenotype : Bone marrow and peripheral blood smear findings were both morphologically consistent with acute myeloid leukemia (AML).
Immunophenotype : Flow cytometry of the bone marrow sample showed a myeloblast population representing 33% of the cells that were positive for CD34, CD33, CD117, CD11b, CD11c, CD13, and cytoplasmic MPO.
Rearranged Ig Tcr : No.
Electron microscopy : not performed
Precise diagnosis : Acute Myeloid Leukemia, NOS (WHO, 2016).
Date of diagnosis: 12-2017
Treatment : The patient began induction chemotherapy regimen on 1/7/2018 consisting of 7 days of daily cytarabine infusion and 3 days of daily daunorubicin. On 2/15/2018 he was treated for refractory AML with a five-day course of mitoxantrone, etoposide, and cytarabine.
Complete remission : None
Treatment related death : -
Relapse : Remission never achieved.
Status : Alive 03-2018
Survival : 3 month(s)
Sample : Bone marrow aspirate. ; culture time : 24 h ; banding : GTG band level: 350-400
Results : 47,XY,t(12;13)(p13;q12),+21 [20]
Karyotype at relapse : Karyotype following completion of induction chemotherapy 2/7/2018; 46,XY,t(12;13)(p13;q12)[3]/47,XY,t(12;13)(p13;q12),+21[8]/47,XY,+8,t(12;13)(p13;q12)[4]/ 48,XY,+8, t(12;13)(p13;q12),+21[5] [Figure 1]
Other molecular cytogenetics technics : Fluorescence in situ hybridization (FISH) using ETV6 LSI break apart probe (Abbott Molecular, Des Plaines, IL USA).
Other molecular cytogenetics results : Fluorescence in situ hybridization (FISH) with EVT6 probe revealed one fusion signal and split signal corresponding to the t(12;13)(p13;q12) however, the partner gene on chromosome 13q12 was not tested [Figures 2].
Other molecular studies
technics : Next generation sequencing (NGS) using a myeloid 54-gene panel.
results : A nonsense variant (.c.2693G>A) in the ASXL1 gene was detected using the Illumina TruSight Myeloid Panel: Nonsense variants in ASXL1 gene are associated with poor prognosis (Metzeler et al, 2011).
G-banded karyotype one month after induction chemotherapy showing t(12;13), trisomy chromosomes 8 and 21
FISH with Vysis LSI ETV6 break apart probe showing a fused signal on an unaffected chromosome 12 and split green and orange signals representing the abnormal chromosomes 12 and 13 respectively (arrows)
The t(12;13)(p13;q12) is very rare in hematological malignancies with only 14 cases including the present case have been reported [Table 1]. Six cases were diagnosed with myeloproliferative neoplasms with eosinophilia (MPNeo), five had AML, and the remaining three were pediatric ALL [see Table1 for references]. Molecular characterization of the t(12;13) breakpoints revealed the rearrangement of ETV6/12p13 gene in 9/14 cases. On the other hand, FLT3 gene was implicated as the involved partner gene on chromosome 13 in five cases. All five were diagnosed with MPNeo, nevertheless the disease was rapidly fatal in three patients [Table 1]. FTL3 encodes a member of the receptor tyrosine kinase subclass III family of receptors, which is expressed in early hematopoietic progenitor cells (Gilliland & Griffin, 2002; Stirewalt & Radich 2003). Mutations in FTL3 gene are found in approximately 30% of AML cases, yet this gene is rarely involved in translocations. Vu et al reported the first case of t(12;13)(p13;q12) in MPNeo, with the translocation resulting in the creation of an ETV6-FLT3 fusion gene. Reciprocal ETV6/FLT3 and FLT3/ETV6 transcripts were detected by RT-PCR; however, at the protein level, only ETV6/FLT3 was expressed in the patient's leukemic cells (Vu et al, 2006). The putative oncogenic function gained as a result of the ETV6-FLT3 fusion is the constitutive activation of the tyrosine kinase domains of FLT3. One case of t(12;13)(p13;q12)-related AML involving a ETV6-CDX2 fusion has been described as well (Chase et al, 1999). Although FISH results in the present case revealed the involvement of ETV6 gene in the t(12;13) translocation, it is unknown whether a specific gene may have been affect at the 13q12 locus.
Unlike FLT3 gene, ETV6/12p13 translocations is commonly detected in a wide spectrum of hematological malignancies lymphoid and myeloid; with at least 48 chromosomal bands and 30 ETV6 partner genes have been reported. The chimeric oncoprotein resulted from the t(12;13) may have a therapeutic implications. Although the ETV6-FLT3 positive leukemia has shown some sensitivity to FLT3 inhibitors, more cases are needed to appreciate the response.
Table 1; Clinical data on patients reported with t(12;13)(p13;q12)
Case #Age/SexDiagnosisGenes involvedClinical StatusSurvival (months)Reference
168Y/FMPN-eoETV6-FLT3Deceased21Vu et al.,  2006
240Y/FMPN-eoETV6-FLT3Alive - CR11Falchi et al.,  2014
360Y/MMPN-eoETV6-FLT3Deceased7Walz et al.,  2011
449Y/MMPN-eoNRDeceased11Chiyoda et al.,  1994
529Y/MMPN-eoETV6-FLT3Deceased13Walz et al., 2011
633Y/MT-ALL and MPN-eoETV6-FLT3Alive - CR72Chonabayashi, et al., 2013
75Y/MALLNRAlive - CR24Keene, 1987
89YALLNRAlive - CRNRHeerema et al., 2000
917Y/FALLETV6-?Deceased29Wlodarska et al., 1987
1062Y/FMDS-RAEBNRNRNRKnapp et al., 1985
1151Y/MAML-M0ETV6-?NRNRTosi et al., 1998
1240Y/MTherapy-related AMLNRDeceased1Clavio et al., 2001
1366Y/MAMLETV6-CDX2Deceased40Chase, 1999
1461Y/MAMLETV6-?Alive3Present case 2018

ALL: F; female: M; male; acute lymphoblastic leukemia; AML: acute myeloid leukemia; CR: complete remission; MDS-RAEB: myelodysplastic syndrome with refractory anemia and excess blasts; MPN-eo: myeloproliferative neoplasms with eosinophilia; NR: not reported; PTCL: peripheral T-cell lymphoma; Y: years.
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1. Citation

This paper should be referenced as such : D>
Perry WR, Schloff D, Mohamed AN
Acute myeloid leukemia with t(12;13)(p13;q12) and ETV6 involvement; Case report and review of literature
Atlas Genet Cytogenet Oncol Haematol. in press
On line version :

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Nov 28 17:10:12 CET 2018

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