t(4;11)(q23;p15) NUP98/RAP1GDS1

Identity

ICD-Topo	C420,C421,C424
ICD-Morpho	9837/3 T lymphoblastic leukaemia/lymphoma
ICD-Morpho	9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id	1191
Note	The t(4;11)(q23;q15) is a rare but recurrent translocation strongly associated with T-cell acute lymphoblastic leukemia (T-ALL). This translocation results in a novel gene fusion of NUP98/11p15 and RAP1GDS1/4q23 genes [Figure 1]. Therefore, t(4;11)(q23;p15) is NOT a variant of the t(4;11)(q21;q23) involving the AFF1 and KMT2A (MLL) genes, as previously presumed.
	Figure 1; Left; Partial karyotype showing t(4;11)(q23;p15), Right; FISH showing a double fusion pattern of NUP98-RAP1GDS1 genes.

Clinics and Pathology

Disease	The t(4;11)(q23;p15) is mostly described in an early precursor T-cell ALL of thymic origin. Only two cases with acute myeloid leukemia (AML) were reported with this translocation; the t(4;11)(q?13;p15) with NUP98/RAP1GDS1 fusion expression was identified in a patient with AML-M0 at time of diagnosis. Whereas the second case was with AML-M4, in which the t(4;11)(q23;p15) was detected at relapse with a normal karyotype at diagnosis.
Phenotype / cell stem origin	Bone marrows are hypercellular with a massive infiltration (~90%) with lymphoblasts of L1 or L2 morphology. Whereas different markers are tested for each case, leukemic cells are generally positive for CD3, CD5, CD7, CD10, TdT, and thymic associated marker CD1a, negative or partially expressing CD2, CD4, and CD8. One or more myeloid markers CD11b, CD13, and/or CD33 are co-expressed in some patients. This suggests that NUP98/RAP1GDS1 fusion occurs in subset of T-ALL originated from an early progenitor with a potential to express mature T-cell antigens as well as myeloid markers.
Epidemiology	Patient's ages are ranged from 6 to 60 years, with a predominance of younger individuals (60% < = 25 years) as is classic for T-cell ALL. None of the patients with this translocation was an infant. The t(4;11)(q23;p15) seems to be extremely rare and its exact incidence in leukemia is difficult to establish. In large studies, t(4;11) was identified in approximately 2% adult and in 0.3% children with T-ALL while other studies have failed to detect a single case.
Clinics	Most patients present with a high WBC counts with a high proportion of blasts, generalized lymphadenopathy and mediastinal mass but hepatospenomagaly is less frequent.
Prognosis	The risk associated with t(4;11)(q23;p15.4) is not well determined due to low number of cases although most patients with this translocation had a short survival.

Cytogenetics

Note	Karyotype is relatively simple with t(4;11)(q23;p15) a sole abnormality in 5/13 cases (Table 1).
Cytogenetics Morphological	Table 1: Reported acute leukemia cases with t(4;11)(q21-q23;p15) and NUP98/RAP1GDS1 gene fusion. Patient Leukemia Age/Sex WBC 109/L Karyotype Fusion Genes Outcome References 1 T-ALL L1 21/M 423 46,XY,t(4;11)(q21;p15),+2mar NUP98/RAP1GDS1 Relapsed after 2 matched BMT; died 43 M Hussey et al., 1999 2 T-ALL L1 25/F 1.8 46,XX,t(4;11)(q21;p14-15), del(12)(p13),+del(13)(q12q14) NUP98/RAP1GDS1 Failure of induction; Died 1M later Hussey et al., 1999 3 T-ALL L2 49/M 169 46,XY,t(4;11)(q21;p15),del(5)(q13q31) NUP98/RAP1GDS1 BM remission, early relapse, died 14 M Hussey et al., 1999 4 T-ALL L2 16/F 34 47,XX,t(4;11)(q21;p15),+8 NUP98/RAP1GDS1 CR, followed by BMT; 7 m+ Mecucci et al., 2000 5 T-ALL L2 38F 35 47,XX,t(4;11)(q21;p15),+mar NUP98/RAP1GDS1 CR, relapsed in 8 m; died after  BMT Mecucci et al. 2000 6 AML-M0 60/F 3.9 46- t(4;11)(q1?3;p15),?der(8)(p?) NUP98/RAP1GDS1 CR; relapsed and died 8m after diagnosis van Zutven et al, 2006 7 T-ALL 15/M 72.8 46,XY,t(4;11)(q23;p15),del(9)(p13) NUP98/RAP1GDS1 CR obtained, survival 7M+ Present case, 2015
Additional anomalies	One or two additional abnormalities were seen in 8/13 cases including del(12p) in two cases; del(5q), del(9p) , del(13q) , or trisomy 8 in a single case each.
Variants	t(1;4;11)(p32;q21;p15) was reported in one case.

Genes involved and Proteins

Gene Name	RAP1GDS1
Location	4q23
Dna / Rna	RAP1, GTP-GDP dissociation stimulator 1 (RAP1GDS1) is a gene that encodes a protein that functions as a stimulatory GDP/GTP exchange protein with GTPase activity. Fusions, missense mutations, nonsense mutations, silent mutations, frameshift deletions, and in-frame deletions are observed in cancers such as endometrial cancer , intestinal cancer, and skin cancer .
Protein	RAP1GDS1 encodes a 558-amino acid protein with a molecular mass of 61.1 kD. The product of the RAP1GDS1 gene, usually referred to as smgGDS, has guanine nucleotide exchange factor activity. It stimulates the conversion of inactive GDP-bound from small GTPases to the active GTP-bound form. It has been speculated that smgGDS might also play a role in nucleocytoplasmic transport, as smgGDS is composed of multiple armadillo repeats that are thought to mediate protein-protein interactions. SmgGDS has been described as a "master regulator" of small GTPases, such as RHOA , RAC1 , RAP1A , RAP1B , and KRAS . SmgGDS controls the activities of these GTPases through several mechanisms, most notably by controlling their prenylation and trafficking to cell membranes. The ability of smgGDS to regulate the cell cycle in multiple cancer cell lines with different mutational profiles indicates the importance of this protein as a key regulator of malignancy. SmgGDS is overexpressed in multiple types of cancer, including non-small cell lung carcinoma , prostate cancer , pancreatic cancer and breast cancer , making SmgGDS is an attractive target for cancer therapeutics.

Gene Name	NUP98
Location	11p15.4
Dna / Rna	NUP98 is one of several genes located in the imprinted gene domain of chromosome 11p15. Combined haploinsufficiency of NUP98 and RAE1 has been shown to result in premature separation of sister chromatids, leading to severe aneuploidy. NUP98 plays roles in gene expression, mitotic spindle formation, and cell cycle progression. NUP98 gene is fused to a large number of "partner genes" caused primarily by balanced translocations and inversions which are associated with a wide variety of hematological malignancies including AML and MDS (de novo and therapy related), CML-blast crisis, and pre T- ALL. To date, no NUP98 fusion gene has been described in B-cell malignancies. At least 30 different partner genes are reported to fuse with NUP98; 50% of which are homeobox genes. Approximately 10% of patients with NUP98 fusions have T-ALL; most commonly, these malignancies are associated with NUP98-RAP1GDS1 gene fusions. This suggests that different partner genes are associated with different leukemia, although such associations are rarely exclusive. Although NUP98 breakpoints in these translocations are variable located between introns 9 to 14, a chimeric transcript consisting of the 5' portion of NUP98 fused in-frame to the 3' portion of the partner genes is generated in all.
Protein	NUP98 gene encodes two alternatively spliced mRNA variants: NUP98 and NUP98-NUP96 that are cleaved to produce two distinct nucleoporins, NUP98 and NUP96. The NUP98 is a 98 kDa protein component of the nuclear pore complex (NPC) family which is involved in the trafficking of RNA and protein between the nucleus and cytoplasm. The NUP98 protein contains two partially characterized functional domains: a GLFG repeat region, which serves as a nuclear transport receptor docking surface, and a GLEBS domain, which mediates the interaction with the RAE1 mRNA nuclear export factor. Both domains are located within the N-terminal portion of NUP98. The chimeric NUP98 protein that results from translocations always retains the intact N-terminal GLFG repeats of NUP98 and the C-terminal domain of the partner protein. NUP96 is a scaffold component of the NPC.

Result of the chromosomal anomaly

Hybrid gene

Note	Of the 13 cases reported in the literature with t(4;11)(q23;q15); seven cases showed NUP98/RAP1GDS1 gene fusion while the status of these genes were not tested in the remaining five cases (Table 1).

Fusion Protein

Description	T(4;11) generates two reciprocal chimeric products; chimeric 5'NUP98 -3'RAP1GDS1 transcript produces a novel protein composed of the N-terminal portion of the NUP98 protein and the entire smgGDS which is anticipated to promote leukemogenesis. However, the reciprocal 5' RAP1GDS1-3'NUP98 transcript is often but not always expressed.

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.
Case Report	T-cell acute lymphoblastic leukemia with t(4;11)(q23;p15) and NUP98/RAP1GDS1 gene fusion: Case report and review of literature.

Bibliography

Molecular evaluation of the NUP98/RAP1GDS1 gene frequency in adults with T-acute lymphoblastic leukemia

Cimino G, Sprovieri T, Rapanotti MC, Foà R, Mecucci C, Mandelli F

Haematologica 2001 Apr;86(4):436-7

PMID 11325654

t(4;11)(q21;p15), including one complex translocation t(1;4;11)(p32;q21;p15), in adult T-cell acute lymphoblastic leukemia

Douet-Guilbert N, Morel F, Le Bris MJ, Herry A, Le Calvez G, Marion V, Berthou C, De Braekeleer M

Leuk Res 2003 Oct;27(10):965-7

PMID 12860018

NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights

Gough SM, Slape CI, Aplan PD

Blood 2011 Dec 8;118(24):6247-57

PMID 21948299

The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia

Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A

Blood 1999 Sep 15;94(6):2072-9

PMID 10477737

A variant translocation between chromosomes 4 and 11, t(4q;11p) in a child with acute leukemia

Inoue S, Tyrkus M, Ravindranath Y, Gohle N

Am J Pediatr Hematol Oncol 1985 Summer;7(2):211-4

PMID 3842567

NUP98 gene fusions in hematologic malignancies

Lam DH, Aplan PD

Leukemia 2001 Nov;15(11):1689-95

PMID 11681408

t(4;11)(q21;p15) translocation involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia

Mecucci C, La Starza R, Negrini M, Sabbioni S, Crescenzi B, Leoni P, Di Raimondo F, Krampera M, Cimino G, Tafuri A, Cuneo A, Vitale A, Foà R

Br J Haematol 2000 Jun;109(4):788-93

PMID 10929031

NUP98 fusion oncoproteins promote aneuploidy by attenuating the mitotic spindle checkpoint

Salsi V, Ferrari S, Gorello P, Fantini S, Chiavolelli F, Mecucci C, Zappavigna V

Cancer Res 2014 Feb 15;74(4):1079-90

PMID 24371226

SmgGDS-558 regulates the cell cycle in pancreatic, non-small cell lung, and breast cancers

Schuld NJ, Hauser AD, Gastonguay AJ, Wilson JM, Lorimer EL, Williams CL

Cell Cycle 2014;13(6):941-52

PMID 24552806

The role of NUP98 gene fusions in hematologic malignancy

Slape C, Aplan PD

Leuk Lymphoma 2004 Jul;45(7):1341-50

PMID 15359631

A t(4;11)(q21;p15) in a case of T-cell lymphoma and a case of acute myelogenous leukemia

Thangavelu M, Huang B, Lemieux M, Tom W, Richkind KE

Cancer Genet Cytogenet 2002 Jan 15;132(2):109-15

PMID 11850070

Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene

van Zutven LJ, Onen E, Velthuizen SC, van Drunen E, von Bergh AR, van den Heuvel-Eibrink MM, Veronese A, Mecucci C, Negrini M, de Greef GE, Beverloo HB

Genes Chromosomes Cancer 2006 May;45(5):437-46

PMID 16419055

Citation

This paper should be referenced as such :

Mohamed AN

t(4;11)(q23;p15) NUP98/RAP1GDS1;

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Anomalies/t0411q23p15ID1191.html

History of this paper:

Viguié, F. t(4;11)(q21;p15). Atlas Genet Cytogenet Oncol Haematol. 2002;6(4):301-302.

http://documents.irevues.inist.fr/bitstream/handle/2042/37906/07-2002-t0411q21p15ID1191.pdf

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes

NUP98

RAP1GDS1

Translocations implicated (Data extracted from papers in the Atlas)

	t(4;11)(q23;p15) NUP98/RAP1GDS1

External links

NUP98 (11p15.4) RAP1GDS1 (4q23)

NUP98 (11p15.4) RAP1GDS1 (4q23)

Mitelman database	t(4;11)(q23;p15) [Case List]    t(4;11)(q23;p15) [Association List] Mitelman database (CGAP - NCBI)
arrayMap	Morph ( 9837/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap	Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
Mitelman database	NUP98/RAP1GDS1 [MCList]  NUP98 (11p15.4) RAP1GDS1 (4q23)
TICdb	NUP98/RAP1GDS1  NUP98 (11p15.4) RAP1GDS1 (4q23)
Disease database	t(4;11)(q23;p15) NUP98/RAP1GDS1

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