t(1;9)(q24;q34) RCSD1/ABL1

2016-09-01   Adriana Zamecnikova , Adriana Zamecnikova 

1.Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait; annaadria@yahoo.com
2.Inserm U613, Laboratoire de Cytogenetique, Faculte de Medecine et des Sciences de la Sante, Universite de Bretagne Occidentale, 22, avenue Camille Desmoulins, CS 93837, F-29238 Brest cedex 3, France

Abstract

Review on t(1;9)(q24;q34) translocation, with data on clinics, and the genes involved.

Clinics and Pathology

Disease

B-cell precursor ALL with expression of CD79a+, CD19+, CD10+, TdT (Mustjoki et al., 2009; Collette et al., 2015 )

Epidemiology

12 cases with an ABL1 split by FISH and/or RCSD1/ABL1 fusion, aged 5 to 40 years (median age 15 years); male predominance (8 males and 4 females); among them 1 with ABL1-positive biphenotypic ALL in which, however, the partner gene has not been identifed.

Cytology

Hyperleukocytosis (WBC range at diagnosis 24 to 470 x 109, median 110 x 109); bone marrow blasts ranging from 58 to 95%.

Prognosis

Poor response to induction chemotherapy and in addition to induction failure, a high risk of relapse including patients after bone marrow transplantation. B-ALL patients with the RCSD1/ABL1 fusion are characterized by susceptibility to tyrosine kinase inhibitor therapy (imatinib, dasatinib, ponatinib) and may achieve transient clinical effects as well as long time remission (Table 1; Data from De Braekeleer et al., 2013; Perwein et al., 2016)
 Sex/
Age		DiagnosisWBC
(x109/L)		PB/BM blasts (%)Genetic testing resultsTherapy

Survival (months)

1 M/15 BAL 12295/ NA46,XY,t(1;9)(q23.3~q25;q34)
ABL1-rearranged (FISH)		Chemotherapy10 died
2* M/11 B-ALL647/92 46,Y,add(X)(p22),t(1;9)(q24;q34)
ABL1-rearranged (FISH)
RCSD1-ABL1		Chemotherapy, BMT, relapsed 2 years after the initial treatment 97
3 40/MB-ALL 24 34/80 46,XY,t(1;9)(q24;q34)
RCSD1-ABL1		Chemotherapy + dasatinib, BMT
Chemotherapy + dasatinib/ imatinib at relapse		 66
4 F/18 B-ALL 11087/ 92 t(1;9)(q24;q34)
ABL1-rearranged (FISH)
RCSD1-ABL1		NA NA
5F/15 B-ALL 348 NA/NA46,XX,t(1;9)(q24;q34)
RCSD1-ABL1		Chemotherapy, BMT at 4, 35 and 84 months following relapse.84 died
6 M/31 B-ALL 146 90/NA 46,XY,t(1;9)(q23;q34),inv(2)(p21q33)
Developed: 45,XY,t(1;9),inv(2),t(5;16)(q33;q24), dic(18;20)(p11;q11) and
46,XY,t(1;9),inv(2),t(5;16),dic(18;20),der(19)t(17;19)(q21;p13),+21 
RCSD1-ABL1		Chemotherapy, transient clinical effects with imatinib, and dasatinib. 6.5 died
7 M/16 B-ALL 48 NA/ NA RCSD1-ABL1 identified by RNA-sequence analysis NANA
8 M/18 B-ALL 470 52/58 46,XY,t(1;9)(q24;q34)
RCSD1-ABL1		No compliance to therapy 12+
9 M/6 B-ALL108NA/ NA46,XY,t(1;9)(q23;q34)
ABL1-rearranged
RCSD1-ABL1		Chemotherapy + imatinib, poor response to chemotherapy1
10 F/26B-ALL2684/8646,XX,t(1;9)(q24;q34)
RCSD1-ABL1		Chemotherapy +dasatinib, BMT, relapse
Chemotherapy +ponatinib, BMT
Ponatinib monotherapy, relapse		25 died
11 F/15 B-ALL25145/NA46,XX,t(1;9)(q24;q34)
IKS deletion		Chemotherapy + dasatinib BMT 8 died
12 M/15B-ALL6971/9546,XY,t(1;9)(q31?;q34)
RCSD1-ABL1		Chemotherapy + imatinib 2 months after relapse: sustained clinical remission163

Abbreviations: WBC., white blood cells; PB., peripheral blood; BM., bone marrow; M., male; F., female; ALL., acute lymphocytic leukemia; * at relapse; BMT., bone marrow transplantation.
1. Gonzales et al., 2004; 2. De Braekeleer et al., 2011; 3. Mustjoki et al., 2009; 4. Zamecnikova et al., 2010; De Braekeleer et al., 2013; 5. De Braekeleer et al., 2011; 6. Inokuchi et al., 2011; 7. Roberts et al., 2012; 8. De Braekeleer et al., 2013; 9. Roberts et al., 2014; 10. Collette et al.,2015; 11. Kamran et al., 2015; 12. Perwein et al., 2016.

Cytogenetics

Atlas Image
Figure 1. Top - courtesy Adriana Zamecnikova and Soad al Bahar: (A) Partial G-banded karyotypes showing the t(1;9)(q24;q34) and fluorescence in situ hybridization with LSI BCR/ABL1 (Vysis/Abott, US) probe showing the split of the ABL1 signal (red). A: Dual-color FISH using RP11-83J21 (labeled in spectrum orange) and RP11-232M22 (labeled in spectrum green) showing two fusion genes. FISH, fluorescence in situ hybridization. B: Probes. Bottom - courtesy Etienne De Braekeleer and Marc De Braekeleer: R-banded karyotype showing the t(1;9)(q24;q34) translocation. Dual-color FISH using RP11-83J21 (labeled in spectrum orange). Probes and RP11-232M22 (labeled in spectrum green) showing two fusion genes. FISH, fluorescence in situ hybridization. LSI bcr/abl dual extra-signal (ES) color probe (Abbott, Rungis, France) and BAC Probes. RP11-83J21 (chromosome 9) and RP11-232M22, RP11-928F1, RP11-138P14, RP11-652E14, RP11-64D9 (chromosome 1). All the probes that were used to find the breakpoint on der(1).

Genes Involved and Proteins

Gene name
ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)
Location
9q34.12
Dna rna description
The ABL gene is aproximately 225 kb in size and is expressed as a 7-kb mRNA transcript, with alternatively spliced first exons, exons 1b and 1a, respectively, spliced to the common exons 2-11. Exon 1b is approximately 200 kb 5-prime of exon 1a.
Protein description
The 145-kD ABL protein is classified as a nonreceptor tyrosine kinase. When the N-terminal region of the ABL protein is encoded by exon 1a, the protein is believed to be localized in the nucleus, while when encoded by exon 1b, the resulting N-terminal glycine would be myristylated and thus postulated to direct that protein to the plasma membrane.
Gene name
RCSD1 (RCSD domain containing 1)
Location
1q24.2
Dna rna description
Eyers et al. (2005) cloned for the first time the human RCSD1, which they called CAPZIP. A 416-amino acid protein was deduced and they calculated a molecular mass of 44.5 kD. Northern blot analysis resulted in a major 3.4-kb transcript and a minor 7-kb transcript that is highly expressed in skeletal muscle and weakly in cardiac muscle. CAPZIP is detected in several lymphoid organs, including spleen, thymus, peripheral blood leukocytes, lymph node, and bone marrow.
Protein description
Eyers et al. (2005) found many properties of rabbit Capzip. It interacted specifically with the F-actin capping protein CapZ. This protein was phosphorylated by : MAPKAPK2 and SAPK3 (MAPK12), on ser108 by SAPK3 and SAPK4 (MAPK13) and on ser68, ser83, and ser216 by JNK1 alpha-1 (MAPK8) in vitro. This team also found that stress induced by hyperosmotic shock and anisomycin, a protein synthesis inhibitor, stimulated the phosphorylation of CAPZIP in human cell lines and induced the dissociation of CAPZIP from CAPZ in Jurkat human T cells. This phenomenon may regulate the ability of CapZ to remodel actin filament.

Result of the Chromosomal Anomaly

Description

RCSD1/ABL1. In-frame fusions of first three exons of RCSD1 to ABL1 exon 4 to 11 and alternatively spliced RCSD1/ABL1 consisting of the first two exons of RCSD1 fused to exon 4 of ABL1 lacking RCSD1 exon 3 (Mustjoki et al., 2009).

Detection protocole

FISH detection.

Description

The RCSD1/ABL1 fusion gene encode the tyrosine kinase domain of ABL1. The chimeric protein contains part of the SH2 domain of ABL1, the SH1 domain (that has tyrosine kinase function), the 3 nuclear localization signal domains, the 3 DNA-binding regions and the F-actin-binding domain. Notably, unlike most of the previously described chimeric genes involving ABL1 that fuse with exon 2 of ABL1 (containing ABL1 exons 2 and 3), the RCSD1/ABL1 protein contains only a truncated ABL1 protein starting from the exon 4-encoded region, therefore retains only a part of the ABL SH2 domain (with tyrosine kinase function), predicting its association with ALL rather than chronic myeloid leukemia (Mustjoki et al., 2009; De Braekeleer et al., 2013; Collette et al., 2015).

Oncogenesis

The RCSD1 gene, which codes a protein kinase substrate, CapZIP (CapZ-interacting protein), is found in immune cells, splenocytes and muscle. It is possible that the interaction between CapZIP and CapZ affects the cell ability to remodel actin filament assembly. CapZIP is phosphorylated when cells are exposed to various cellular stresses, which activate the kinase cascade. The interaction between CapZIP and CapZ would be lost when CapZIP is phosphorylated. So, RCSD1 would be involved in the remodeling of the actin cytoskeleton, which is an important step in mitosis. The probable formation of the ABL1-RCSD1 fusion gene could result in an alteration of the cellular function by affecting the cytoskeleton regulation, which could be an important step in leukemogenesis.

Highly cited references

Pubmed IDYearTitleCitations
214350022011ABL1 fusion genes in hematological malignancies: a review.32
278555582017Diagnostic evaluation of RNA sequencing for the detection of genetic abnormalities associated with Ph-like acute lymphoblastic leukemia (ALL).7
231686142013Acute lymphoblastic leukemia associated with RCSD1-ABL1 novel fusion gene has a distinct gene expression profile from BCR-ABL1 fusion.7
271259822016Imatinib-induced long-term remission in a relapsed RCSD1-ABL1-positive acute lymphoblastic leukemia.6
218632872011RCSD1-ABL1-positive B lymphoblastic leukemia is sensitive to dexamethasone and tyrosine kinase inhibitors and rapidly evolves clonally by chromosomal translocations.6
197940962009A novel dasatinib-sensitive RCSD1-ABL1 fusion transcript in chemotherapy-refractory adult pre-B lymphoblastic leukemia with t(1;9)(q24;q34).6
280577402017Dasatinib and allogeneic stem cell transplantation enable sustained response in an elderly patient with RCSD1-ABL1-positive acute lymphoblastic leukemia.5
266009552015RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia.1
354840802022Clinico-hematological and Outcome Profile of Pediatric B-other-ALL and BCR::ABL1-like pre-B-ALL: An Integrated Genomic Study From North India.0

Bibliography

Pubmed IDLast YearTitleAuthors
257684062015Drug response profiling can predict response to ponatinib in a patient with t(1;9)(q24;q34)-associated B-cell acute lymphoblastic leukemia.Collette Y et al
231686142013Acute lymphoblastic leukemia associated with RCSD1-ABL1 novel fusion gene has a distinct gene expression profile from BCR-ABL1 fusion.De Braekeleer E et al
151934482004A t(1;9)(q23.3 approximately q25;q34) affecting the ABL1 gene in a biphenotypic leukemia.González García JR et al
218632872011RCSD1-ABL1-positive B lymphoblastic leukemia is sensitive to dexamethasone and tyrosine kinase inhibitors and rapidly evolves clonally by chromosomal translocations.Inokuchi K et al
266009552015RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia.Kamran S et al
197940962009A novel dasatinib-sensitive RCSD1-ABL1 fusion transcript in chemotherapy-refractory adult pre-B lymphoblastic leukemia with t(1;9)(q24;q34).Mustjoki S et al
252077662014Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.Roberts KG et al
216410352011Chromosomal translocation t(1;9)(q24;q34) in acute lymphoblastic leukemia patient involving the ABL1 gene.Zámečníkova A et al

Summary

Fusion gene

RCSD1/ABL1 RCSD1 (1q24.2) ABL1 (9q34.12) M t(1;9)(q24;q34)|RCSD1/ABL1 RCSD1 (1q24.2) ABL1 (9q34.12) TIC

Citation

Adriana Zamecnikova ; Adriana Zamecnikova

t(1;9)(q24;q34) RCSD1/ABL1

Atlas Genet Cytogenet Oncol Haematol. 2016-09-01

Online version: http://atlasgeneticsoncology.org/haematological/2109/t(1;9)(q24;q34)-rcsd1-abl1

Historical Card

2007-11-01 t(1;9)(q24;q34) RCSD1/ABL1 by  Etienne De Braekeleer,Marc De Braekeleer 

Inserm U613, Laboratoire de Cytogenetique, Faculte de Medecine et des Sciences de la Sante, Universite de Bretagne Occidentale, 22, avenue Camille Desmoulins, CS 93837, F-29238 Brest cedex 3, France