| 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. |
| 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 |
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| 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. |
| Gene Name | RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1) |
| 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. |
| 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 |
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| t(4;11)(q21;p15), including one complex translocation t(1;4;11)(p32;q21;p15), in adult T-cell acute lymphoblastic leukemia |
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| NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights |
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| Blood 2011 Dec 8;118(24):6247-57 |
| PMID 21948299 |
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| 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 |
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| A variant translocation between chromosomes 4 and 11, t(4q;11p) in a child with acute leukemia |
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| NUP98 gene fusions in hematologic malignancies |
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| PMID 11681408 |
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| t(4;11)(q21;p15) translocation involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia |
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| NUP98 fusion oncoproteins promote aneuploidy by attenuating the mitotic spindle checkpoint |
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| Cancer Res 2014 Feb 15;74(4):1079-90 |
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| SmgGDS-558 regulates the cell cycle in pancreatic, non-small cell lung, and breast cancers |
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| Cell Cycle 2014;13(6):941-52 |
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| The role of NUP98 gene fusions in hematologic malignancy |
| Slape C, Aplan PD |
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| PMID 15359631 |
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| 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 |
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| 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 |
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