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inv(2)(p23q13) RANBP2/ALK

t(2;2)(p23;q13) RANBP2/ALK

Written2014-11Eul-Ju Seo
Department of Laboratory Medicine, University of Ulsan College of Medicine, Asian Medical Center, Seoul, Korea

Abstract The fusion of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene in myeloid malignancies is extremely rare. The RANBP2-ALK fusion of inv(2)(p23q13)/t(2;2)(p23;q13) combined with monosomy 7 has been reported in a few patients diagnosed with acute myelomonocytic leukemia or juvenile myelomonocytic leukemia.

Keywords RANBP2, ALK, monosomy 7, myelomonocytic leukemia

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 1710
Note The inv(2)(p23q13) is an example of two variants involving ALK gene at 2p23 and RANBP2 gene at 2q13, inv(2) and t(2;2). The RANBP2/ALK fusion combined with monosomy 7 is associated with myeloid malignancies. This chromosomal rearrangement has also been observed in inflammatory myofibroblastic tumors (IMT).
 
  inv(2)(p23q13) G-banding. Courtesy Eul-Ju Seo.

Clinics and Pathology

Disease Myeloid lineage: acute myelomonocytic leukemia, juvenile myelomonocytic leukemia
Phenotype / cell stem origin Three cases of acute myelomonocytic leukemia (AML-M4), two cases of juvenile myelomonocytic leukemia (JMML).
Epidemiology Five cases reported to date: 3M/2F; age 3.5-75 years (median 16 years).
Clinics The five patients with inv(2)(p23q13) or t(2;2)(p23;q13) were two women (31, 75 years) and one 16 year-old male with acute myelomonocytic leukemia, and two boys (3.5, 8 years) with juvenile myelomonocytic leukemia.
The median WBC was 85.3 x 109/L (range, 55.6-143.6 x 109/L) and median monocyte count was 27 x 109/L (range, 20-55 x 109/L).
Cytology Bone marrow: marked hypercellularity, granulocytic hyperplasia with leukemic blasts of myelomonocytic morphology.
Immunohistochemistry for ALK protein: strong staining of the nuclear membrane in leukemic cells.
Prognosis In four cases, early relapse after 1 to 6 months; in two cases, early death after 2 and 14 months. Two pediatric patients were alive at 6 and 8 years after stem cell transplantation.

Cytogenetics

Cytogenetics Morphological Four out of five cases showed inv(2)(p23q13), and one case of JMML had t(2;2)(p23;q13). Interestingly, the monosomy 7 abnormality was observed in all cases, while it has not yet been reported in IMT cases.
 
  FISH with ALK break apart probe. A split signal indicates pericentric inversion in the inv(2)(p23q13), showing ALK gene rearrangement. Courtesy Eul-Ju Seo.
Additional anomalies Monosomy 7 (100%).

Genes involved and Proteins

Gene Name ELL
Location 2p23
Protein 1620 amino acids; 177 kDa; receptor tyrosine kinase.
Gene Name RANBP2
Location 2q12.3
Protein 3224 amino acids; 358 kDa; large RAN-binding protein that immunolocalizes to the nuclear pore complex; E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I. Involved in facilitation of protein import and export, sumoylation of protein cargoes, intracellular trafficking, and energy maintenance.

Result of the chromosomal anomaly

Hybrid gene
Description 5' RANBP2 - 3' ALK.
Transcript In-frame fusion transcript between RANBP2 exon 18 and ALK exon 20 in all cases.
  
Fusion Protein
Description 1430-amino acid RANBP2-ALK fusion protein; The first 867 N-term amino acids of RANBP2 fused to the 563 C-term amino acids of ALK (i.e. the leucine-rich domain, including the leucine zipper, of RANBP2 and the entire cytoplasmic portion of ALK with the tyrosine kinase domain).
Expression Localisation Nuclear membrane.
Oncogenesis RANBP2 protein contains an N-terminal 700-residue leucine-rich region predicted to mediate homo-oligomerization of the RANBP2-ALK oncoprotein, leading to the activation of the ALK kinase catalytic function.
  

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

RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia.
Lim JH, Jang S, Park CJ, Cho YU, Lee JH, Lee KH, Lee JO, Shin JY, Kim JI, Huh J, Seo EJ.
Cancer Genet. 2014 Jan-Feb;207(1-2):40-5. doi: 10.1016/j.cancergen.2013.12.003. Epub 2014 Jan 21. (REVIEW)
PMID 24613277
 
inv(2)(p23q13)/RAN-binding protein 2 (RANBP2)-ALK fusion gene in myeloid leukemia that developed in an elderly woman.
Maesako Y, Izumi K, Okamori S, Takeoka K, Kishimori C, Okumura A, Honjo G, Akasaka T, Ohno H.
Int J Hematol. 2014 Feb;99(2):202-7. doi: 10.1007/s12185-013-1482-x. Epub 2013 Dec 4.
PMID 24307515
 
ALK fusion genes in children with atypical myeloproliferative leukemia.
Rottgers S, Gombert M, Teigler-Schlegel A, Busch K, Gamerdinger U, Slany R, Harbott J, Borkhardt A.
Leukemia. 2010 Jun;24(6):1197-200. doi: 10.1038/leu.2010.18. Epub 2010 Apr 29.
PMID 20428197
 

Citation

This paper should be referenced as such :
Seo EJ
inv(2)(p23q13) RANBP2/ALK; t(2;2)(p23;q13) RANBP2/ALK;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/inv2p23q13ID1710.html


Translocations implicated (Data extracted from papers in the Atlas)

 inv(2)(p23q13) RANBP2/ALK
 t(2;2)(p23;q13) RANBP2/ALK

External links

RANBP2 (2q12.3) ALK (2p23.2)

RANBP2 (2q12.3) ALK (2p23.2)

RANBP2 (2q12.3) ALK (2p23.2)

Mitelman databaseinv(2)(p23q13) [Case List]    inv(2)(p23q13) [Association List] Mitelman database (CGAP - NCBI)
Mitelman databaset(2;2)(p23;q13) [Case List]    t(2;2)(p23;q13) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionRANBP2/ALK RANBP2 (2q12.3) ALK (2p23.2)   [fusion415]   [fusion416]   [fusion417]   [fusion418]  
Mitelman databaseRANBP2/ALK [MCList]  RANBP2 (2q12.3) ALK (2p23.2)
TICdbRANBP2/ALK  RANBP2 (2q12.3) ALK (2p23.2)
 
Disease databaseinv(2)(p23q13) RANBP2/ALK
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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