Download Leukaemia Section t(1;21)(p22;q22) RUNX1/CLCA2 Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Leukaemia Section
Short Communication
t(1;21)(p22;q22) RUNX1/CLCA2
Amélie Giguère, Josée Hébert
Quebec Leukemia Cell Bank and Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital,
Montreal, Quebec, H1T 2M4, Canada (AG, JH)
Published in Atlas Database: June 2012
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0121p22q22ID1608.html
DOI: 10.4267/2042/48236
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Treatment
Clinics and pathology
The pediatric patient was treated with cytarabine,
mitoxantrone and amsacrine. At complete remission, he
underwent an allogeneic stem cell transplantation with
a conditioning regimen including etoposide and total
body irradiation. At relapse, the boy underwent a
second bone marrow transplantation.
The adult patient was treated with a standard induction
chemotherapy regimen (infusional cytarabine combined
with daunorubicine) and two cycles of consolidation
therapy with high doses cytarabine, followed by a
reduced intensity allogeneic stem cell transplantation.
The t(1;21) positive t-AML was not treated with
chemotherapy. The patient received palliative care.
Disease
Therapy-related acute myeloid leukemia (t-AML)
Epidemiology
Two AML cases positive for the t(1;21)(p22;q22) were
reported, a 9 year-old boy (Nadal et al., 2008) and a 64
year-old man (Giguère and Hébert, 2010).
Clinics
The 9 year-old boy presented in September 2004 with
an initial diagnosis of acute myeloid leukemia with
maturation (AML-M2) with a normal karyotype.
In December 2004, he underwent an allogeneic bone
marrow transplantation and then relapsed in June 2006.
At
relapse,
the
karyotype
was
46,XY,t(1;21)(p22;q22)[15]/46,XX[5].
The adult patient developed a de novo AML-M2 with
an abnormal karyotype 45,XY,-7[17]/46,XY[3] in
December 2005.
He received a standard induction and consolidation
chemotherapy followed by an allogeneic hematopoietic
stem cell transplantation.
In August 2007, he developed a t(1;21)(p22;q22)
positive t-AML.
Complete blood count showed a white blood cell count
of 16.4 x 109/L, hemoglobin of 86 g/L and platelet
count of 34 x109/L. The bone marrow aspirate showed
52% of blast cells.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11)
Evolution
The boy was alive in April 2012 (Nadal, personal
communication). The adult patient died one month and
18 days following t-AML development.
Prognosis
Undetermined.
Genetics
Note
FLT3-ITD (FLT3 internal tandem duplication)
mutation was detected in the pediatric patient's
leukemic cells and was absent in the adult patient's
cells.
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t(1;21)(p22;q22) RUNX1/CLCA2
Giguère A, Hébert J
Partial GTG-banded karyotype showing derivative chromosomes 1 and 21 involved in the t(1;21)(p22;q22).
Metaphasic FISH using the LSI RUNX1-RUNX1T1 dual color translocation probe (Abbott Molecular). Three green signals (21q22,
RUNX1 gene) are shown (arrows), indicating the presence of a RUNX1 rearrangement. Two normal red signals (8q22, RUNX1T1 gene)
were observed.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11)
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t(1;21)(p22;q22) RUNX1/CLCA2
Giguère A, Hébert J
Additional anomalies
Cytogenetics
The t(1;21) was the sole anomaly in t-AML cells.
Cytogenetics morphological
Can be easily identified using G-banded chromosomes.
Genes involved and proteins
Cytogenetics molecular
RUNX1
FISH using the RUNX1-RUNX1T1 probe showed
splitted signals located on derivative chromosomes 1
and 21.
RUNX1 rearrangement was confirmed using the RP11299D9 BAC probe (BACPAC Resources Center)
(Giguère and Hébert, 2010).
Location
21q22
DNA/RNA
The RUNX1 gene contains 8 coding exons spanning
260 kilobases (kb) of genomic DNA.
The RUNX1 gene and protein are represented. Exons 3 to 5 code for the DNA binding Runt homology domain (RHD) whereas exons 7
and 8 encode the transcriptional regulatory domain which includes activation (TA) and inhibitory domains (ID).
The CLCA2 gene and protein are represented. The calcium-activated chloride channel (CLCA), the von Willebrand factor type A domain
(VWA) and a domain of unknown function (DUF1973) are encoded by amino acids 8 to 265, 312 to 470 and 494 to 674 respectively,
according to the PFAM website (http://pfam.sanger.ac.uk).
Main fusion transcript resulting in a fusion of RUNX1 exons 1-6 to CLCA2 exons 2-14.
Transcription orientation: telomere to centromere.
Protein
RUNX1 is a conserved member of the RUNX family
and is a master regulator of hematopoiesis through
activation or repression of lineage-specific genes.
The protein was proposed to function as a regulator of
chloride current and to act as a potential tumor
suppressor in breast cancer cells (Gruber and Pauli,
1999; Elble and Pauli, 2001).
Result of the chromosomal
anomaly
CLCA2
Location
1p22.3
DNA/RNA
The CLCA2 gene contains 14 exons which spans 32 kb
of genomic DNA. Transcription orientation: telomere
to centromere.
Protein
CLCA2 is a member of the calcium-activated chloride
channel family.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11)
Hybrid gene
Description
5' RUNX1-CLCA2 3'.
Transcript
At least six out-of-frame fusion transcripts were
identified (Giguère and Hébert, 2010).
854
t(1;21)(p22;q22) RUNX1/CLCA2
Giguère A, Hébert J
Nadal N, Stephan JL, Cornillon J, Guyotat D, Flandrin P,
Campos L. RUNX1 rearrangements in acute myeloblastic
leukemia
relapsing
after
hematopoietic
stem
cell
transplantation. Cancer Genet Cytogenet. 2008 Jan
15;180(2):168-9
Fusion protein
Note
In this case, RUNX1-CLCA2 fusion transcripts lead to
truncated RUNX1 proteins (Giguère and Hébert, 2010).
References
Giguère A, Hébert J. CLCA2, a novel RUNX1 partner gene in a
therapy-related leukemia with t(1;21)(p22;q22). Cancer Genet
Cytogenet. 2010 Oct 15;202(2):94-100
Gruber AD, Pauli BU. Tumorigenicity of human breast cancer
is associated with loss of the Ca2+-activated chloride channel
CLCA2. Cancer Res. 1999 Nov 1;59(21):5488-91
This article should be referenced as such:
Giguère A, Hébert J. t(1;21)(p22;q22) RUNX1/CLCA2. Atlas
Genet Cytogenet Oncol Haematol. 2012; 16(11):852-855.
Elble RC, Pauli BU. Tumor suppression by a proapoptotic
calcium-activated chloride channel in mammary epithelium. J
Biol Chem. 2001 Nov 2;276(44):40510-7
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