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t(9;14)(q33;q32) IGH/LHX2

Written2013-11Nathalie Nadal, Elise Chapiro
Laboratoire d'hematologie, CHU Hopital Nord, F-42055 St Etienne cedex 2, France (NN); Service d'Hematologie Biologique, Hopital Pitie-Salpetriere, APHP, Universite Pierre et Marie Curie-Paris 6, France (EC)

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Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Atlas_Id 1659
 
  A. Conventional karyotype: partial R and G-banded karyotype. The derivative chromosomes of translocations t(9;14)(q33;q32) and t(9;22)(q34;q11) are denoted by solid and dotted arrows, respectively.
B. FISH: representative metaphase hybridized with dual color break-apart IGH probe (Abbott, Rungis, France). A fusion signal is seen on normal chromosome 14 (large arrows), a red signal on derivative chromosome 14 (small solid arrows) and a green signal on derivative chromosome 9 (small dotted arrows).
C. FISH: representative metaphase hybridized with a BCR/ABL ES probe (Abbott). A green signal is seen on a normal chromosome 22 (large arrows), and two fusion signals on derivative chromosomes 9 and 22 (small dotted arrows), confirming the BCR-ABL1 rearrangement with a breakpoint in the mBCR region. A red signal is observed on derivative chromosome 14 (small solid arrows), indicating that the breakpoint of t(9;14) was centromeric to the ABL1 gene in chromosome 9.

Clinics and Pathology

Disease Chronic myeloid leukemia (CML) in B-cell lymphoid blast crisis
Phenotype / cell stem origin B cell phenotype (CD19, CD10) with 2 aberrant myeloid markers (CD13 and CD33).
Etiology Unknown.
Epidemiology Only one case to date, a 10-year-old male patient (Nadal et al., 2012).
Clinics Lymphadenopathies, enlarged spleen and liver. Central nervous system involvement.
Cytology High WBC with blast cells (44%), myelemia, eosinophilia and basophilia. Bone marrow aspiration showed 60% of undifferentiated blast cells with persistence of the granulocytic lineage.
Treatment The patient was treated according to the European protocol ESPHALL (imatinib, asparaginase, vincristine, vindesine, daunorubicin, aracytine, VP16, ifosfamide, and methotrexate, followed by an allograft).
Evolution After induction, minimal residual disease (MRD) detection by CMF and by molecular analysis was negative, whereas RT-PCR for BCR-ABL1 transcript was still positive. Chromosomal examination showed the presence of one metaphase out of 30 with only the t(9;22)(q34;q11), suggesting that the t(9;14) translocation was a secondary chromosomal abnormality.
Thus, the chemotherapy had eradicated the lymphoblast cells but a CML clone persisted, further supporting the diagnosis of CML in BC.
By 7 months after diagnosis, the patient underwent allogenic stem cell transplantation from his HLA-matched sister. At 2 years post-transplantation, the patient was alive and well. BCR-ABL1 transcript was undetectable (<0.001%).

Cytogenetics

Additional anomalies The t(9;14)(q33;q32) translocation appears as a secondary abnormality occurring at acutisation of a CML with the usual t(9;22)(q34;q11) with a breakpoint in the mBCR region. The latest is usually observed in BCR-ABL1+ de novo acute lymphoblastic leukemia but is rare in CML.
i(7)(q10), present in 2 out of the 20 metaphases analyzed using conventional karyotype, and in 3/100 metaphases using FISH (7q22/7q36 Dual-Color probe, Kreatech Diagnostics).

Genes involved and Proteins

Gene NameLHX2 (LIM homeobox 2)
Location 9q33.3
Note LIM homeobox gene LHX2 is a member of the LIM homeobox family of transcription factors characterized by a DNA binding homeodomain and a cystein-rich LIM-domain. LHX2, initially identified as an early marker in B-lymphocyte differentiation (Xu et al., 1993), is involved in the neurogenesis, hair follicle, and hematopoietic development (Porter et al., 1997).
Gene NameIGH (Immunoglobulin Heavy)
Location 14q32.33

Result of the chromosomal anomaly

Hybrid gene
Note The translocation links sequence located 148 kb centromeric of LHX2 on chromosome 9 to JH6 segment on chromosome 14.
  
Fusion Protein
Note No fusion protein.
Oncogenesis LHX2 juxtaposition with the IGH locus results in strong over-expression of LHX2, which may have contributed to the rapid progression in the blastic phase. It has been shown that over-expression of LHX2 in murine hematopoietic precursors leads to the development of chronic myeloproliferative disorders (Richter et al., 2003). Thus, transcriptional deregulation of LHX2 plays a recurrent role in leukemogenesis.
  

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.

Bibliography

LHX2 deregulation by juxtaposition with the IGH locus in a pediatric case of chronic myeloid leukemia in B-cell lymphoid blast crisis.
Nadal N, Chapiro E, Flandrin-Gresta P, Thouvenin S, Vasselon C, Beldjord K, Fenneteau O, Bernard O, Campos L, Nguyen-Khac F.
Leuk Res. 2012 Sep;36(9):e195-8. doi: 10.1016/j.leukres.2012.05.013. Epub 2012 Jun 22.
PMID 22727509
 
Lhx2, a LIM homeobox gene, is required for eye, forebrain, and definitive erythrocyte development.
Porter FD, Drago J, Xu Y, Cheema SS, Wassif C, Huang SP, Lee E, Grinberg A, Massalas JS, Bodine D, Alt F, Westphal H.
Development. 1997 Aug;124(15):2935-44.
PMID 9247336
 
Lhx2 expression in hematopoietic progenitor/stem cells in vivo causes a chronic myeloproliferative disorder and altered globin expression.
Richter K, Pinto do O P, Hagglund AC, Wahlin A, Carlsson L.
Haematologica. 2003 Dec;88(12):1336-47.
PMID 14687986
 
Identification of a human LIM-Hox gene, hLH-2, aberrantly expressed in chronic myelogenous leukaemia and located on 9q33-34.1.
Wu HK, Heng HH, Siderovski DP, Dong WF, Okuno Y, Shi XM, Tsui LC, Minden MD.
Oncogene. 1996 Mar 21;12(6):1205-12.
PMID 8649822
 
LH-2: a LIM/homeodomain gene expressed in developing lymphocytes and neural cells.
Xu Y, Baldassare M, Fisher P, Rathbun G, Oltz EM, Yancopoulos GD, Jessell TM, Alt FW.
Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):227-31.
PMID 7678338
 

Citation

This paper should be referenced as such :
Nadal, N ; Chapiro, E
t(9;14)(q33;q32) IGH/LHX2
Atlas Genet Cytogenet Oncol Haematol. 2014;18(6):438-440.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0914q33q32ID1659.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(9;14)(q33;q32) IGH/LHX2

External links

IGH (14q32.33) LHX2 (9q33.3)

Mitelman databaset(9;14)(q33;q32) [Case List]    t(9;14)(q33;q32) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9975/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseIGH/LHX2 [MCList]  IGH (14q32.33) LHX2 (9q33.3)
 
Disease databaset(9;14)(q33;q32) IGH/LHX2
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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