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

2014-11-01   Eul-Ju Seo 

1.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.

Clinics and Pathology

Phenotype stem cell 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.
Atlas Image
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
ALK (anaplastic lymphoma receptor tyrosine kinase)
Location
2p23
Protein description
1620 amino acids; 177 kDa; receptor tyrosine kinase.
Gene name
RANBP2 (RAN binding protein 2)
Location
2q12.3
Protein description
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

Description

5 RANBP2 - 3 ALK.

Transcript

In-frame fusion transcript between RANBP2 exon 18 and ALK exon 20 in all cases.

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.

Bibliography

Pubmed IDLast YearTitleAuthors
246132772014RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia.Lim JH et al
243075152014inv(2)(p23q13)/RAN-binding protein 2 (RANBP2)-ALK fusion gene in myeloid leukemia that developed in an elderly woman.Maesako Y et al
204281972010ALK fusion genes in children with atypical myeloproliferative leukemia.Röttgers S et al

Summary

Fusion gene

RANBP2/ALK RANBP2 (2q12.3) ALK (2p23.2) COF 415 416 417 418|RANBP2/ALK RANBP2 (2q12.3) ALK (2p23.2) M inv(2)(p23q13) t(2;2)(p23;q13)|RANBP2/ALK RANBP2 (2q12.3) ALK (2p23.2) TIC

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).
Atlas Image
inv(2)(p23q13) G-banding. Courtesy Eul-Ju Seo.

Citation

Eul-Ju Seo

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

Atlas Genet Cytogenet Oncol Haematol. 2014-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1710/inv(2)(p23q13)

External Links