Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals   Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

do you wish to send a case report ?

(Paper co-edited with the European LeukemiaNet)
T-cell acute lymphoblastic leukemia with t(7;14)(p15;q11.2)/HOXA-TCRA/D and biallelic deletion of CDKN2A. Case report and literature review
Written2014-01Jonathon Mahlow, Salah Ebrahim, Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine and Detroit Medical Center, Detroit MI, USA
Age and sex : 9 year(s) old male patient.
Previous History : no preleukemia
no previous malignant disease
no inborn condition of note
Organomegaly : no hepatomegaly ; splenomegaly ; enlarged lymph nodes ; no central nervous system involvement
Note : Positive for splenomegaly, bilateral enlarged kidneys, large mediastinal mass, extensive lymphadenopathy of intrathoracic, retroperitoneal, cervical, and axillary regions. Cerebral spinal fluid negative for malignant cells.
WBC : 31.6 x 109/L ; Hb : 8.6 g/dL ; platelets : 15 x 109/L; blasts : 65 % .
Bone marrow : Dry tap
Note : Peripheral blood showed anemia, thrombocytopenia and leukocytosis.
Cyto pathology classification
Cytology : Peripheral blood smear showed large L2 lymphoblasts with nucleoli, normochromic, normocytic RBCs and markedly decreased platelets.
Immunophenotype : Flow cytometric analysis of peripheral blood demonstrated an abnormal CD45dim circulating lymphoblasts (75%) expressing CD2, CD5, CD7, CD8, CD10, cytoplasmic CD3, TdT and partially expressing weak CD30. Overall, these findings were consistent with T-cell malignancy.
Rearranged Ig Tcr : No rearrangements of TCRB and TCRA/D genes by FISH.
Electron microscopy : Not performed.
Precise diagnosis : T-cell acute lymphoblastic leukemia (T-ALL).
Date of diagnosis: 09-2013
Treatment : Patient was treated with COG-AALL00434 protocol including vincristine, daunorubicin hydrochloride, prednisone, pegaspargase, and intrathecal cytarabine and methotrexate.
Complete remission was obtained
Treatment related death : -
Relapse : -
Status : Alive 01-2014
Survival : 4 month(s)
Sample : Peripheral blood ; culture time : 24 h, and 48hrs unstimulated cultures ; banding : GTG
Results : 46, XY,del(6)(q14q21),t(7;14)(p15;q11.2),del(9)(p13)[12]/92,idemx2,[7]/46,XY[1] (Figure 1)
Other molecular cytogenetics technics : Fluorescence in situ hybridization (FISH)
FISH using Vysis LSI BCR/ABL, CDKN2A/CEP-9 and TCRA/D, as well as Cytocell TCRB DNA probes was performed on peripheral blood harvested pellet. FISH analysis revealed four copies for TCRB/7q34, TRA/D/14q11.2, BCR/22q11.2, and ABL/9q34 in approximately 50% of cells, representing the pseudotetraploid cell line observed by karyotype. No BCR/ABL gene fusion was detected in any cell line. The hybridization with the CDKN2A/CEP9 probe set produced nullisomy (biallelic loss) of the CDKN2A in 79% of cells but four copies of the control CEP-9 in 44% of cells and two copies in the remaining 35% while the normal cells had 2 copies of each (Figure 2).
To verify the results of chromosome analysis with respect to t(7;14), confirmatory FISH was performed using Signature Genomic DNA probes BAC probes RP11-1132K14/7p15 (orange) covering the HOXA cluster genes and CTD-2555K7/14q11.2 (green) laying immediately telomeric to the TCRA/D/14q11.2 coding region. The hybridization revealed a fusion pattern; one fusion signal in the pseudodiploid and two fusion signals in the pseudotetraploid cells (Figure 3).
Array Comparative Genomic Hybridization (aCGH)
Genomic DNA was isolated from peripheral blood using a Puregene kit (Gentra Systems, Minneapolis, MN). The aCGH was performed using a genome wide oligonucleotide + single nucleotide polymorphism based microarray containing 180K-features (SurePrint G3 GGXChip + SNP v1.0 4x180k Agilent Technologies, St Clara, CA). The microarray slide was scanned by Agilent G2565 CA microarray scanner system with data imported to aCGH Analytics Software (Genoglyphix™; Signature Genomic Laboratories). The array design and genomic coordinates are based on NCBI build 37 (hg19).
The aCGH revealed a 33.3Mb terminal monoallelic deletion of chromosome 9p13.3->pter, with 1.39 Mb biallelic deletions in the 9p21.3 region which spans the CDKN2A gene locus (Figure 4). It also detected a large 20.7 Mb interstitial deletion at del(6)(q14.1q16.2) and 1.34 Mb duplication within the 4q32.1 region.
Figure 1: G-banded karyotype of the pseudodiploid cell line demonstrating del(6q) (hollow arrow), t(7;14)(p15;q11.2) (thin arrows), and del(9p) (solid arrow).
Figure 2: FISH was performed using CDKN2A (orange) and the control CEP 9 (green) DNA probe set. The hybridization revealed biallelic loss of CDKN2A in an abnormal metaphase (long arrow) while the normal diploid interphase cell had two copies of each (short arrow).
Figure 3: FISH of a t(7;14) carrying metaphase cell demonstrating fusion of HOXA-TCRA/D gene regions (thin arrow).
Figure 4: aCGH plot for chromosome 9 showing compound deletions. The light blue region indicates a terminal monoallelic deletion of 33.3 Mb of 9p while dark blue region points to biallelic deletion within the 9p21.3.
The patient here presented with progressive cough and neck mass. He was found to have an elevated WBC count with concomitant anemia and thrombocytopenia. Assessment of peripheral blood revealed the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL). Chromosome analysis showed two clones, pseudodiploid and pseudotetraploid, both exhibiting t(7;14)(p15;q11.2), del(6)(q14q21), and del(9)(p13) (Figure 1). However, the pseudotetraploid clone had two copies of these abnormalities indicating it was derived from duplication of the pseudodiploid clone. FISH confirmed juxtaposing of HOXA/7p15 and TCRD/14q11.2 genes in the t(7;14) carrying leukemic cells (Figure 3).
Homeobox (HOX) genes encode transcription factors which act as key regulators in embryonic development and normal hematopoiesis. Recently, the HOXA gene cluster at chromosome 7p15 has been described as a new recurrent breakpoint that occurs in up to 3% of T-ALL. The inv(7)(p15q34) and t(7;7)(p15;q34) place HOXA under the control of T-cell specific enhancer of TCRB, leading to upregulation of HOXA genes particularly HOXA10 and HOXA11. Another rare translocation is t(7;14)(p15;q11.2), previously described in a 29-year-old patient with T-ALL. The translocation resulted in colocalization of HOXA-TCRD genes, and generalized overexpression of the HOXA genes. However the leukemic clone of this case had also t(10;11)(p14;q21), and expressed CALM-AF10 fusion transcript. Therefore, it was concluded that the existence of both HOXA-TCRD and CALM-AF10 in the same leukemic cells may contribute to the global expression of HOXA genes. The t(7;14) in a 31-year old female with T-ALL was also cited but not well documented in a technical report by Garipidou et al 1991.
The present case is believed to be the only other well described case with t(7;14)(p15;q11.2)/HOXA-TCRD translocation. However, our case was lacking t(10;11) which may make the two cases different in clinical presentation and response to therapy. Biallelic deletion of CDKN2A/9p21 as documented by aCGH and FISH was also found in our case (Figures 2, 4). Deletion of CDKN2A, tumor suppressor gene, is the most frequent genomic aberration occurs in over 70% of T-ALL which emphasizes the importance of CDKN2A inactivation in the development of this leukemia. A study pooling 907 individual cases of ALL has demonstrated that CDKN2A deletion, mono- or biallelic, is an independent risk factor for the development of ALL irrespective of cell lineage (B or T-cell). However, the prognostic significance of CDKN2A deletion in cases of pediatric T-cell ALL is currently unknown due to its frequent association with other recurrent cytogenetic abnormalities. The deletion CDKN2A/9p21 has been previously shown to accompany the common yet nonspecific finding of del(6q), which was also present in this case.
In summary, the t(7;14)(p15;q11.2) translocation is extremely rare resulting in an aberrant juxtaposing of HOXA-TCRD genes. Therefore, TCRD/14q11.2 may consider as a new variant partner for activation of HOXA/7p15 in T-ALL. Although the expression of HOXA genes was not tested in the present case, we assume it was upregulated as documented previously in HOXA-TCRD case and HOXA-TCRB cases.
Internal links
Atlas Cardt(7;14)(p15;q11)
Abnormalities of the long arm of chromosome 6 in childhood acute lymphoblastic leukemia.
Hayashi Y, Raimondi SC, Look AT, Behm FG, Kitchingman GR, Pui CH, Rivera GK, Williams DL.
Blood. 1990 Oct 15;76(8):1626-30.
PMID 2207332
The use of fluorodeoxyuridine synchronization for cytogenetic investigation of acute lymphoblastic leukemia.
Garipidou V, Secker-Walker LM.
Cancer Genet Cytogenet. 1991 Mar;52(1):107-11.
PMID 1826229
Effects of HOX homeobox genes in blood cell differentiation.
Magli MC, Largman C, Lawrence HJ.
J Cell Physiol. 1997 Nov;173(2):168-77. (REVIEW)
PMID 9365517
6q deletions in acute lymphoblastic leukemia and non-Hodgkin's lymphomas.
Merup M, Moreno TC, Heyman M, Ronnberg K, Grander D, Detlofsson R, Rasool O, Liu Y, Soderhall S, Juliusson G, Gahrton G, Einhorn S.
Blood. 1998 May 1;91(9):3397-400.
PMID 9558398
HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL).
Soulier J, Clappier E, Cayuela JM, Regnault A, Garcia-Peydro M, Dombret H, Baruchel A, Toribio ML, Sigaux F.
Blood. 2005 Jul 1;106(1):274-86. Epub 2005 Mar 17.
PMID 15774621
HOXA cluster deregulation in T-ALL associated with both a TCRD-HOXA and a CALM-AF10 chromosomal translocation.
Bergeron J, Clappier E, Cauwelier B, Dastugue N, Millien C, Delabesse E, Beldjord K, Speleman F, Soulier J, Macintyre E, Asnafi V.
Leukemia. 2006 Jun;20(6):1184-7.
PMID 16572206
T-cell acute lymphoblastic leukemia.
Chiaretti S, Foa R.
Haematologica. 2009 Feb;94(2):160-2. doi: 10.3324/haematol.2008.004150. (REVIEW)
PMID 19181788
A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups.
Sulong S, Moorman AV, Irving JA, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart AR, Bailey S, Bown NP, Hall AG, Harrison CJ.
Blood. 2009 Jan 1;113(1):100-7. doi: 10.1182/blood-2008-07-166801. Epub 2008 Oct 6.
PMID 18838613
Leukemogenic transformation by HOXA cluster genes.
Bach C, Buhl S, Mueller D, Garcia-Cuellar MP, Maethner E, Slany RK.
Blood. 2010 Apr 8;115(14):2910-8. doi: 10.1182/blood-2009-04-216606. Epub 2010 Feb 3.
PMID 20130239
Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk.
Sherborne AL, Hosking FJ, Prasad RB, Kumar R, Koehler R, Vijayakrishnan J, Papaemmanuil E, Bartram CR, Stanulla M, Schrappe M, Gast A, Dobbins SE, Ma Y, Sheridan E, Taylor M, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Moorman AV, Harrison CJ, Tomlinson IP, Richards S, Zimmermann M, Szalai C, Semsei AF, Erdelyi DJ, Krajinovic M, Sinnett D, Healy J, Gonzalez Neira A, Kawamata N, Ogawa S, Koeffler HP, Hemminki K, Greaves M, Houlston RS.
Nat Genet. 2010 Jun;42(6):492-4. doi: 10.1038/ng.585. Epub 2010 May 9.
PMID 20453839
The molecular basis of T cell acute lymphoblastic leukemia.
Van Vlierberghe P, Ferrando A.
J Clin Invest. 2012 Oct 1;122(10):3398-406. doi: 10.1172/JCI61269. Epub 2012 Oct 1. (REVIEW)
PMID 23023710


This paper should be referenced as such :
Free journal version : [ pdf ]   [ DOI ]
On line version :

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Dec 5 19:12:04 CET 2020

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals   Portal   Teaching   

For comments and suggestions or contributions, please contact us