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(Paper co-edited with the European LeukemiaNet)
t(2;11)(q31;p15) in therapy related myeloid neoplasm: case report and review of literature
Written2013-06Amarpreet Bhalla, Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI, USA
Age and sex : 59 year(s) old female patient.
Previous History : no preleukemia
no previous malignant disease
no inborn condition of note
Patient diagnosed with breast cancer in 1995, treated with adjuvant chemotherapy consisting of 4 cycles of CAF (cyclophosphamide, doxorubicin and fluorouracil) and CMF (cyclophosphamide, methotrexate and fluorouracil) followed by tamoxifen for 6 years. On 6/2006, she had evidence of recurrence and subsequent liver, ribs, and skull metastases. She was treated with several other chemotherapies such as taxotere, gemzar, fluvestrant, taxol, bevacizumab and xeloda, and radiation therapy. On 11/2011, she developed brain metastasis and was successfully treated with gamma knife. Over her last year, she was on oral cyclophosphamide and doxorubicin.
Organomegaly : no hepatomegaly ; no splenomegaly ; no enlarged lymph nodes ; central nervous system involvement (brain metastasis);
WBC : 58.7 x 109/L ; Hb : 8.7 g/dL ; platelets : 47 x 109/L;
Note : Peripheral blood showed anemia, thrombocytopenia, neutrophilic leukocytosis with absolute monocytosis.
Blasts: 0.9 X109/L, promyelocytes: 0.9 X109/L, myelocytes: 1.5 X109/L, metamyelocytes: 2.3 X109/L, bands: 4.1X109/L, neutrophils: 29.7 X109/L, monocytes: 17 X109/L; lymphocytes: 2.3 X109/L.
Bone marrow biopsy revealed a hypercellular marrow with 80% cellularity, multilineage dysplasia, 10.2% immature monocytes and 3.2% myeloblasts. CD34/CD117 showed approximately 10% immature myeloid/monocytic cells. CD64 highlighted the expanded monocytic component. In addition there were scattered metastatic tumor cells positive for AE1/AE3, mammoglobin and BRST1 by immunohistochemistry supporting primary breast origin.
Cyto pathology classification
Cytology : Therapy related myeloid neoplasm best classified as therapy related myelodysplastic /acute myeloid leukemia (t-MDS/AML).
Immunophenotype : Flow cytometric of peripheral blood detected 2% myeloblasts expressing CD13, CD33, CD 34, CD117 and HLA-DR, and partially expressing CD14, CD4, CD11d, CD11c and CD64. In addition there were two monocytes gates detected; 18% monocytes were expressing CD13, CD33, and partially expressing CD4, CD11b, CD11c, CD15, CD117, CD64 and CD14. There was a subpopulation of monocytes representing 6% of gated monocytes were negative CD14, CD19, CD2, CD10, CD7, CD34, CD163 but HLA-DR positive.
Rearranged Ig Tcr : Not performed.
Electron microscopy : Not performed.
Precise diagnosis : Therapy related MDS/AML
Date of diagnosis: 01-2013
Treatment : Only supportive therapy
Complete remission : None
Treatment related death : -
Relapse : -
Status : Dead 02-2013
Sample : Bone marrow aspirate ; culture time : 24 h, unstimulated culture and 48 hrs culture with 10% conditioned medium ; banding : GTG
Results : 46, XX,t(2;11)(q31;p15)[14]/47,XX,t(2;11)(q31;p15),+8[6] (Figure 1)
Other molecular studies
technics : Fluorescence in situ hybridization (FISH) using MDS panel DNA probes included EGR1/5q31, D5S23: D5S721/5p15.2, D7S486/7q31, D7Z1/CEP-7, D8Z2/CEP-8, D20S108/20q12, as well as the LSI MLL dual color break apart DNA probe (Abbott Molecular).
FISH results were consistent with trisomy chromosome 8 in 9% of cells and a normal pattern for the remaining loci.
In addition, dual color FISH using Signature Genomic DNA probes Rp11-387A1/2q31.1 covering HOXD gene cluster including both HOXD11 and HOXD13 genes was labeled SpectrumOrange, while the RP11-120E20/11p15.4 covering NUP98 gene was labeled SpectrumGreen (PerkinElmer, Spokane, WA). The hybridization revealed a fusion signal located on der(2) due to a translocation of NUP98/15p15 (green) to HOXD/2q31(orange) gene region (Figure 2). The remainder of HOXD signal was translocated to 11p15.
Figure 1: G-banded karyotype showing t(2;11)(q31;p15) (arrows).
Figure 2: Dual color FISH analysis performed on a metaphase with t(2;11) using BAC probes for NUP98 (RP11-120E20) labeled in green and for HOXD (RP11387A1) labeled in orange, showed the presence of a fusion signal on der(2) (arrow); two orange signals on der(11) and chromosome 2; single green on normal chromosome 11.
Table 1: Leukemia cases with t(2;11)(q31;p15) previously reported and the present case. Y: Years; Mon: Months; F: Female; M: Male.
The patient presented here was a 59 year old female with a history of breast cancer with several cycles of chemotherapy and radiation therapy due to metastatic recurrences. Seventeen years later, she developed thrombocytopenia along with anemia. Despite the reduction of chemotherapy dosages, her blood cell counts did not recover. Further assessment of bone marrow biopsy revealed the diagnosis of t-MDS/AML with absolute monocytosis and monocytic feature. Chromosome analysis identified t(2;11)(q31;p15) translocation in all metaphases and trisomy 8 as a secondary abnormality in a subpopulation of cells.
NUP98 gene rearrangement as a result of t(2;11)(q31;p15) is rare, described in only 8 patients (including the present one). This translocation resulting in NUP98-HOXD13 gene fusion was first described in a 10 year-old patient with therapy-related AML-M6. Subsequently, five other patients have been reported with t(2;11) leukemia; all described to have a de novo AML M4 including three infants. The same translocation was also reported in a 15 year-old patient with chronic myeloid leukemia in blast crisis (CML BC) (Table 1 case #5). In this report, we present the second patient with t(2;11) who was diagnosed with t-MDS/AML after a long history of treated metastatic breast cancer.
The partner gene fused with NUP98 in leukemia harboring t(2;11) was the homeobox genes HOXD13 in all case, and HOXD11 in one patient (Table 1). The NUP98-HOXD13 and NUP98-HOXD11 fusion transcripts were detected in bone marrow of these patients, respectively. In a mouse model, studies have shown that NUP98-HOXD13 transgenic mice developed MDS similar to human, including peripheral blood cytopenia, ineffective hematopoiesis with dysplasia, and increased apoptosis in bone marrow. Within 14 months, all mice died of either leukemic transformation or severe pancytopenia.
In our patient, FISH showed a fusion pattern suggestive NUP98-HOXD13 or HOXD11 gene fusion but not with certainty since the BAC RP11-387A1 probe covers other HOXD genes in the region (Figure 2).
In Summary, t(2;11)(q31;p13) translocation in leukemia is rare but recurrent, and occurs in de novo AML as well as t-MDS/AML, and six out eight of patients were <15 years including three infants (Table 1). Morphologically this translocation appears to be associated with monocytic features, mostly AML M4. The t(2;11) leads to the generation of leukemogenic NUP98 fusion protein.
Internal links
Atlas Cardt(2;11)(q31;p15) NUP98/HOXD13
NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia.
Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD.
Cancer Res. 1998 Oct 1;58(19):4269-73.
PMID 9766650
Heterogenous fusion transcripts involving the NUP98 gene and HOXD13 gene activation in a case of acute myeloid leukemia with the t(2;11)(q31;p15) translocation.
Arai Y, Kyo T, Miwa H, Arai K, Kamada N, Kita K, Ohki M.
Leukemia. 2000 Sep;14(9):1621-9.
PMID 10995009
Generation of the NUP98-HOXD13 fusion transcript by a rare translocation, t(2;11)(q31;p15), in a case of infant leukaemia.
Shimada H, Arai Y, Sekiguchi S, Ishii T, Tanitsu S, Sasaki M.
Br J Haematol. 2000 Jul;110(1):210-3. (REVIEW)
PMID 10931000
The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15).
Taketani T, Taki T, Shibuya N, Ito E, Kitazawa J, Terui K, Hayashi Y.
Cancer Res. 2002 Jan 1;62(1):33-7.
PMID 11782354
Analysis of translocations that involve the NUP98 gene in patients with 11p15 chromosomal rearrangements.
Kobzev YN, Martinez-Climent J, Lee S, Chen J, Rowley JD.
Genes Chromosomes Cancer. 2004 Dec;41(4):339-52.
PMID 15390187
NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia.
Lin YW, Slape C, Zhang Z, Aplan PD.
Blood. 2005 Jul 1;106(1):287-95. Epub 2005 Mar 8.
PMID 15755899
A complex karyotype, including a three-way translocation generating a NUP98-HOXD13 transcript, in an infant with acute myeloid leukemia.
Hidaka E, Tanaka M, Matsuda K, Ishikawa-Matsumura M, Yamauchi K, Sano K, Honda T, Wakui K, Yanagisawa R, Nakazawa Y, Sakashita K, Shiohara M, Ishii E, Koike K.
Cancer Genet Cytogenet. 2007 Jul 15;176(2):137-43.
PMID 17656257
Backtracking to birth of the NUP98-HOXD13 gene fusion in an infant acute myeloid leukemia.
Emerenciano M, Meyer C, Macedo-Silva ML, de Meis E, Dobbin JA, Marschalek R, Pombo-de-Oliveira MS.
Leukemia. 2011 Jul;25(7):1192-4. doi: 10.1038/leu.2011.51. Epub 2011 Apr 15.
PMID 21494261


This paper should be referenced as such :
Bhalla A, Mohamed AN
t(2;11)(q31;p15) in therapy related myeloid neoplasm: case report and review of literature
Atlas Genet Cytogenet Oncol Haematol. in press
On line version :

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