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CASE REPORTS in HAEMATOLOGY
(Paper co-edited with the European LeukemiaNet)
A case of Acute Lymphoblastic Leukemia with rare t(11;22)(q23;q13)
 
Written2011-10Jill D Kremer, Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI, USA
Clinics
Age and sex : 14 month(s) old male patient.
Previous History : no preleukemia
no previous malignant disease
Patient has hemoglobin S trait
Organomegaly : hepatomegaly ; splenomegaly ; enlarged lymph nodes ; central nervous system involvement ;
Blood
WBC : 33 x 109/L ; Hb : 2.6 g/dL ; platelets : 1 x 109/L; blasts : 72 % .
Bone marrow : 100 bone marrow blast replacement
Cyto pathology classification
Cytology : Acute lymphoblastic leukemia (ALL) with L1 morphology
Immunophenotype : Flow cytometry of bone marrow aspirate identified a dim CD45 lymphoblast population (85%) expressing HLA-DR, CD19 and partially expressing CD10, CD22, CD9 and CD40.
Rearranged Ig Tcr : Not performed.
Pathology : Bone marrow aspirate appeared hypocellular with 95% lymphoblasts of L1 morphology, 2% myeloid series, and 3% erythroid series.
Electron microscopy : Not performed.
Precise diagnosis : CD34 negative B-precursor ALL.
Survival
Date of diagnosis: 01-2011
Treatment : Methotrexate, Cytarabine, Vincristine, Dexamethasone, PEG-aspargase
Complete remission : None
Treatment related death : -
Relapse : -
Status : Alive 10-2011
Survival : 9 month(s)
Karyotype
Sample : Bone marrow aspirate ; culture time : 24 h, without stimulant and 48hr with 10% conditioned medium ; banding : GTG
Results : 46,Y,der(X)t(X;9)(p11.1;q11),add(9)(q11),t(11;22)(q23;q13)[20] (see Figure 1). Post induction bone marrow study demonstrated a normal 46,XY karyotype.
Other molecular studies
technics : Fluorescence in situ hybridization (FISH) using the ALL panel DNA probes including CEP 4, 10, and 17 alpha satellite probes, LSI MLL dual-color break apart probe, BCR/ABL and TEL/AML1 dual-fusion translocation probes was performed (Abbott Molecular, Downers Grove, IL).
results : Hybridization with MLL probe produced a split/translocation pattern in 61% of interphase cells. Metaphase FISH showed that the telomeric region of MLL gene was translocated to 22q13 distal to BCR (Figure 2). The hybridization with the BCR/ABL probe showed two signals each (unfused), however on a previously G-banded metaphase it appeared that the BCR signals remained on chromosome 22 while one ABL signal was translocated to der(X). The remaining probes produced a normal hybridization pattern.
Figure 1: G-banded karyotype showing 46,Y,der(X)t(X;9)(p11.1;q11),add(9)(q11),t(11;22)(q23;q13). Arrows pointed to t(11;22).
Figure 2: FISH. A. Interphase hybridized with LSI MLL dual-color break apart probe showed a split signal pattern of MLL (1O1G1F). B. Metaphase hybridized with BCR/ABL dual-fusion probe showed 2O2G signaling. C. For identification of chromosome 22, the same metaphase subsequently hybridized with LSI MLL probe showing relocation of the telomeric side (orange signal) of MLL to 22q confirming t(11;22)(q23;q13) (arrows). Note: G= green; O= orange; F= fusion.
Comments
The patient described here is a 14 month-old-male presented with an upper respiratory tract infection unresponsive to antibiotics. Subsequently he was diagnosed with high risk B-precursor ALL due to the positivity of MLL/11q23 rearrangement. The patient was started on a Children's Oncology Group induction chemotherapy protocol. Secondary to his high risk status, the patient is being evaluated for a bone marrow transplant. At time of diagnosis chromosome analysis revealed the presence t(11;22)(q23;q13) in all 20 metaphases and rearrangement of the MLL gene.
Translocations involving the MLL/11q23 region are the most common genomic aberrations in infant ALL seen in ~80% of cases (Raimondi, 2004). Generally leukemia harboring MLL translocation is clinically aggressive and associated with poor prognosis. The most common chromosomes involved in 11q23 translocations are t(4;11) followed by t(11;19) and t(9;11). Additionally, leukemia with MLL/11q23 translocations are frequently associated with over expression of FLT3, therefore, targeted therapy inhibitors of FLT3 (a tyrosine kinase) may be beneficial for those patients. Currently there are only three reported cases in the literature with t(11;22)(q23;q13), unlike our case all having secondary acute myeloid leukemia with prior therapy of topoisomerase II inhibitor (table 1). Moreover, rearrangement of the MLL gene and MLL-EP300 fusion gene were demonstrated in those three cases (Ida et al., 1997; Ohnishi et al., 2008; Duhoux et al., 2011). The clinical presentation of our case is quit different from these three cases. Although our case had a rearrangement of the MLL/11q23 gene, the MLL-EP300 fusion gene was not tested. Because the partner genes involved in MLL/11q23 translocations are markedly heterogeneous, it remains unclear whether EP300 or other gene is involved in the present case which may be responsible for the different phenotype of this leukemia.

Table 1: AML cases with t(11;22)(q23;q13) reported in literature.
PatientPrimary MalignancyLeukemiaKaryotypeGene
4 Y/M [2]Non-Hodgkin LymphomaAML M148,XY,+8,+8,t(11;22)(q23;q13)MLL-EP300
5 Y/F [3]NeuroblastomaAML M246,XX,t(1;22;11)(q44;q13;q23),t(10;17)(q22;q21)MLL-EP300
65 Y/M [4]AML with MDSAMML46,XY,t(11;22)(q23;q13)[15]/47,idem,+8[2]MLL-EP300

Internal links
Atlas Cardt(11;22)(q23;q13)
Bibliography
Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13).
Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M, Ohki M, Hayashi Y.
Blood. 1997 Dec 15;90(12):4699-704.
PMID 9389684
 
11q23 rearrangements in childhood acute lymphoblastic leukemia.
Raimondi SC.
Atlas Genet Cytogenet Oncol Haematol. February 2004. URL : http://AtlasGeneticsOncology.org/Anomalies/11q23ChildALLID1321.html .
 
A complex t(1;22;11)(q44;q13;q23) translocation causing MLL-p300 fusion gene in therapy-related acute myeloid leukemia.
Ohnishi H, Taki T, Yoshino H, Takita J, Ida K, Ishii M, Nishida K, Hayashi Y, Taniwaki M, Bessho F, Watanabe T.
Eur J Haematol. 2008 Dec;81(6):475-80. Epub 2008 Sep 6.
PMID 18778367
 
Novel variant form of t(11;22)(q23;q13)/MLL-EP300 fusion transcript in the evolution of an acute myeloid leukemia with myelodysplasia-related changes.
Duhoux FP, De Wilde S, Ameye G, Bahloula K, Medves S, Lege G, Libouton JM, Demoulin JB, A Poirel H.
Leuk Res. 2011 Mar;35(3):e18-20. Epub 2010 Oct 25.
PMID 20980053
 

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