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

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

Written	2007-11	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
Updated	2016-09	Adriana Zamecnikova, Soad al Bahar
		Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait; annaadria@yahoo.com

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

Keywords chromosome 1; chromosome 9; ABL1; RCSD1; B-cell acute lymphoblastic leukemia

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS

ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS

Atlas_Id 2109

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 Diagnosis WBC
(x10^9/L) PB/BM blasts (%) Genetic testing results Therapy
Survival (months)

1 M/15 BAL 122 95/ NA 46,XY,t(1;9)(q23.3~q25;q34)
ABL1-rearranged (FISH) Chemotherapy 10 died

2* M/11 B-ALL 6 47/92 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/M B-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 110 87/ 92 t(1;9)(q24;q34)
ABL1-rearranged (FISH)
RCSD1-ABL1 NA NA

5 F/15 B-ALL 348 NA/NA 46,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 NA NA

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-ALL 108 NA/ NA 46,XY,t(1;9)(q23;q34)
ABL1-rearranged
RCSD1-ABL1 Chemotherapy + imatinib, poor response to chemotherapy 1

10 F/26 B-ALL 26 84/86 46,XX,t(1;9)(q24;q34)
RCSD1-ABL1 Chemotherapy +dasatinib, BMT, relapse
Chemotherapy +ponatinib, BMT
Ponatinib monotherapy, relapse 25 died

11 F/15 B-ALL 251 45/NA 46,XX,t(1;9)(q24;q34)
IKS deletion Chemotherapy + dasatinib BMT 8 died

12 M/15 B-ALL 69 71/95 46,XY,t(1;9)(q31?;q34)
RCSD1-ABL1 Chemotherapy + imatinib 2 months after relapse: sustained clinical remission 163

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

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

Location 9q34

Dna / Rna 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 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

Location 1q24

Dna / Rna 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 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

Hybrid gene
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 FISH detection.

Fusion Protein
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.

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

Drug response profiling can predict response to ponatinib in a patient with t(1;9)(q24;q34)-associated B-cell acute lymphoblastic leukemia

Collette Y, Prébet T, Goubard A, Adélaïde J, Castellano R, Carbuccia N, Garnier S, Guille A, Arnoulet C, Charbonier A, Mozziconacci MJ, Birnbaum D, Chaffanet M, Vey N

Blood Cancer J 2015 Mar 13;5:e292

PMID 25768406

Acute lymphoblastic leukemia associated with RCSD1-ABL1 novel fusion gene has a distinct gene expression profile from BCR-ABL1 fusion

De Braekeleer E, Douet-Guilbert N, Guardiola P, Rowe D, Mustjoki S, Zamecnikova A, Al Bahar S, Jaramillo G, Berthou C, Bown N, Porkka K, Ochoa C, De Braekeleer M

Leukemia 2013 Jun;27(6):1422-4

PMID 23168614

The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ.

Eyers CE, McNeill H, Knebel A, Morrice N, Arthur SJ, Cuenda A, Cohen P

The Biochemical journal. 2005 ; 389 (Pt 1) : 127-135.

PMID 15850461

A t(1;9)(q23

González García JR, Bohlander SK, Gutiérrez Angulo M, Esparza Flores MA, Picos Cárdenas VJ, Meza Espinoza JP, Ayala Madrigal Mde L, Rivera H

3 approximately q25;q34) affecting the ABL1 gene in a biphenotypic leukemia Cancer Genet Cytogenet

PMID 15193448

RCSD1-ABL1-positive B lymphoblastic leukemia is sensitive to dexamethasone and tyrosine kinase inhibitors and rapidly evolves clonally by chromosomal translocations

Inokuchi K, Wakita S, Hirakawa T, Tamai H, Yokose N, Yamaguchi H, Dan K

Int J Hematol 2011 Sep;94(3):255-60

PMID 21863287

RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia

Kamran S, Raca G, Nazir K

Case Rep Hematol 2015;2015:353247

PMID 26600955

A novel dasatinib-sensitive RCSD1-ABL1 fusion transcript in chemotherapy-refractory adult pre-B lymphoblastic leukemia with t(1;9)(q24;q34)

Mustjoki S, Hernesniemi S, Rauhala A, Kähkönen M, Almqvist A, Lundán T, Porkka K

Haematologica 2009 Oct;94(10):1469-71

PMID 19794096

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia

Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil JM, Smith MA, Marcucci G, Bloomfield CD, Mrózek K, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan CG

N Engl J Med 2014 Sep 11;371(11):1005-15

PMID 25207766

Chromosomal translocation t(1;9)(q24;q34) in acute lymphoblastic leukemia patient involving the ABL1 gene

Zámecníkova A

Leuk Res 2011 Sep;35(9):e149-50

PMID 21641035

Citation

This paper should be referenced as such :

Zamecnikova A, al Bahar S

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

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Anomalies/t0109q24q34ID2109.html

History of this paper:

De, Braekeleer E ; De, Braekeleer M. t(1;9)(q24;q34). Atlas Genet Cytogenet Oncol Haematol. 2008;12(6):466-468.

http://documents.irevues.inist.fr/bitstream/handle/2042/38611/11-2007-t0109q24q34ID2109.pdf

Translocations implicated (Data extracted from papers in the Atlas)

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

External links

RCSD1 (1q24.2) ABL1 (9q34.12)
RCSD1 (1q24.2) ABL1 (9q34.12)
Mitelman database t(1;9)(q24;q34) [Case List]    t(1;9)(q24;q34) [Association List] Mitelman database (CGAP - NCBI)
arrayMap Topo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]

Mitelman database RCSD1/ABL1 [MCList]  RCSD1 (1q24.2) ABL1 (9q34.12)

TICdb RCSD1/ABL1  RCSD1 (1q24.2) ABL1 (9q34.12)

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

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

All articles automatic search in PubMed

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For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

ICD-Topo	C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho	9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id	2109

Gene Name	ABL1
Location	9q34
Dna / Rna	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	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
Location	1q24
Dna / Rna	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	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.

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	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.

Mitelman database	t(1;9)(q24;q34) [Case List] t(1;9)(q24;q34) [Association List] Mitelman database (CGAP - NCBI)
arrayMap	Topo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]

Mitelman database	RCSD1/ABL1 [MCList] RCSD1 (1q24.2) ABL1 (9q34.12)
TICdb	RCSD1/ABL1 RCSD1 (1q24.2) ABL1 (9q34.12)

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

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed
All articles	automatic search in PubMed