Received: 26 April 2016

Revised: 17 August 2016

Accepted: 19 August 2016

DOI: 10.1002/pbc.26266

Pediatric
Blood &
Cancer

BRIEF REPORT

The American Society of

Pediatric Hematology/Oncology

Translocation t(8;14)(q24;q11) with concurrent PTEN

alterations and deletions of STIL/TAL1 and CDKN2A/B in a
pediatric case of acute T-lymphoblastic leukemia: A genetic
prole associated with adverse prognosis
Jolanta Skalska-Sadowska1

Magorzata Dawidowska2

Bronisawa Szarzyska-Zawadzka2
Joanna Czerwiska-Rybak3
1 Department of Pediatric Oncology, Hematol-

ogy and Transplantology, University of Medical

Sciences, Pozna, Poland
2 Institute of Human Genetics, Polish Academy of

Sciences, Pozna, Poland

3 Department of Hematology and Bone Marrow

Transplantation, University of Medical Sciences,

Pozna, Poland
Correspondence
Jolanta Skalska-Sadowska, Department of Pediatric Oncology, Hematology and Transplantology,
University of Medical Sciences, Szpitalna 27/33,
60572 Pozna, Poland.
Email: jsk@poczta.onet.eu
Grant sponsor
National Science Centre Poland; Grant number:
2014/15/B/NZ2/03394 and 2013/11/N/NZ5/
03730; EMBO short-term fellowship; Grant
number: ASTF 50-2015.

Magorzata Jarmu-Szymczak2,3

Ludomia Machowska1

Katarzyna Derwich1

Abstract
We report a pediatric case of acute T-lymphoblastic leukemia (T-ALL) with NOTCH1wt , FBXW7wt ,
STIL/TAL1, and PTEN (exons 2, 3, 4, 5) monoallelic deletions, biallelic CDKN2A/B deletion, and
a minor t(8;14)(q24;q11)-positive subclone. Undetectable by a ow cytometric minimal residual disease assay, the t(8;14)(q24;q11) subclone expanded as detected by uorescence in situ
hybridization from 5% at diagnosis to 26% before consolidation and 100% at relapse bearing
a monoallelic deletion (exons 2, 3) with a new frameshift mutation of PTEN and the same set
of remaining molecular alterations. This case documents an unfavorable prognostic potential
of a co-occurrence of this set of molecular genetic events and addresses risk stratication in
T-ALL.
KEYWORDS

MYC, prognostic factors, PTEN, T-ALL, t(8;14)(q24;q11)

INTRODUCTION

STIL/TAL1 and CDKN2A/B were observed, whereas PTEN (exons 2, 3)

was monoallelically deleted with a new frameshift mutation acquired.

Translocation t(8;14)(q24;q11) has been reported in 1% of acute

T-lymphoblastic leukemia (T-ALL) cases and related to unfavorable
prognosis, but its role in treatment stratication is uncertain.1 Investigations of its clinical relevance are based on scattered case reports
including only few with a molecular prole available.
We report a pediatric case of T-ALL in which t(8;14)(q24;q11)
resulting in MYC rearrangement was detected in a minor leukemic
subclone at diagnosis, triggering an early relapse and unfavorable outcome. Concurrent genetic lesions identied at diagnosis
included STIL/TAL1 and PTEN (exons 2, 3, 4, 5) monoallelic deletions
and CDKN2A/B biallelic deletion. At relapse, the same deletions of

CASE PRESENTATION

A 4-year-old male presented with fever, cervical lymphadenopathy,

hepatosplenomegaly, white blood cell (WBC) count of 306 109 /l,
hemoglobin 10.7 g/dl, platelets 53 109 /l, uric acid 12 mg/dl, and lactate dehydrogenase 2,579 IU/l. In bone marrow, 80% of blast cells
were counted with a precursor T-lymphoblastic phenotype according to European Group for Immunological Markers for Leukaemias:
cCD3+, CD3, CD7+, CD2+, CD5dim+, CD4+/, CD8+, CD1a,
TdT+, CD34, HLA DR, TCR/ (where TCR is T-cell receptor),
and TCR/. CNS and mediastinum were not involved. A conven-

Abbreviations: FC-MRD, minimal residual disease assessed by ow cytometry; FISH,

uorescence in situ hybridization; LICs, leukemia-initiating cells; MLPA, multiplex ligation
dependent probe amplication; T-ALL, acute T-lymphoblastic leukemia; TCR, T-cell receptor;
WBC, white blood cell

Pediatr Blood Cancer 2016; 0: 14

tional cytogenetic analysis, performed on 12 metaphases, demonstrated 46,XY,t(8;14)(q24;q11)[4]/46,XY[8] karyotype. Interphase uorescence in situ hybridization (FISH) using a Vysis MYC dual-color

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SKALSKA-SADOWSKA ET AL .

netic analysis demonstrated 46XY,t(8;14)(q24;q11)[20] karyotype in

all studied metaphases. FISH analysis showed MYC rearrangement
in 100% of the analyzed nuclei. Genetic screening revealed monoallelic deletion of STIL/TAL1 and PTEN (exons 2, 3), biallelic deletion of
CDKN2A/B, and PTEN frameshift mutation in exon 7, leading to premature stop codon (Fig. 2B). Despite corticosteroid therapy, the WBC
count increased from 48 to 260 109 /l within 3 days. Cytoreduction
with vincristine (1.5 mg/m) and cyclophosphamide (2,100 mg/mtwo
consecutive days)

was followed by WBC drop to 0.01 109 /l with

clearance of blasts. Although anti-infectious prophylaxis was applied,

febrile neutropenia occurred with subsequent septic shock, and in
spite of intensive treatment, the child died 12 days after cessation of
chemotherapy.

DISCUSSION

The prognostic signicance of molecular genetic abnormalities associated with T-ALL, including those detected in the current case, remains
elusive. We examined outcomes for 28 t(8;14)(q24;q11)-positive TALL cases including 26 children. Eleven of them derived from the only
series of this disease documented so far,1 and the remaining ones
were retrieved from either case reports or research articles published
FIGURE 1

Cytogenetic analysis of bone marrow cells at diagnosis of

T-ALL in a 4-year-old male. (A) The karyogram (GTG-banding) showing t(8;14)(q24;q11.2): derivative chromosomes 8 and 14 (arrows). (B)
Interphase nuclei with one normal signal (yellow) and split signal red
(5 MYC) and green (3 MYC) from MYC break-apart probe

between 1986 and 2014.1,315 Among these 28 cases, the disease

relapsed within 114 months with resistance to further chemotherapy in 14 patients,1,311 two patients died of leukemia/lymphoma 1,12
and another two of toxic complications (time to death: 1 day and 6
weeks).1,3 Despite the postulated dismal prognosis, eight of the 28
t(8;14)(q24;q11)-positive cases showed survival after standard rstline regimens, including six with a long-term follow-up (43 months

break-apart (8q24) probe showed MYC rearrangement in 5% of nuclei

over 5 years).1,5,12,13

(Figs. 1A and 1B). Genes potentially involved in T-cell leukemogen-

TAL1 and CDKN2A/CDKN2B alterations have been considered

esis were studied: STIL/TAL1, LEF1, CASP8AP2, MYB, EZH2, MTAP +

to be associated with trends toward good and poor outcomes,

MLLT3, NUP214-ABL1, LMO1, LMO2, NF1 + SUZ12, PTPN2, PHF6,

respectively.3,11,13 Tumor suppressor gene PTEN abnormalities in pedi-

and CDKN2A/B with multiplex ligation dependent probe amplication

atric T-ALL have been related nonsignicantly to worse outcomes,

technique; and NOTCH1, FBXW7, PTEN, IL7R, FLT3, STAT5B, and WT1

however the results of various studies have been inconsistent.16 A

with Sanger sequencing method. Monoallelic deletions of PTEN (exons

recent report by Jenkinson et al. negated PTEN abnormalities as a

2, 3, 4, 5) and STIL/TAL1 genes, and biallelic deletion of CDKN2A/B,

strong T-ALL prognostic factor, irrespective of NOTCH1/FBXW7/RAS

were the only mutations detected (Fig. 2A). After hydration and ras-

genotype.16 This may raise the question of whether prognosis in T-ALL

buricase reduced uric acid level, the patient was treated accord-

depends rather on a specic set of co-occurring genetic events instead

ing to ALLIC-BFM 2009 chemotherapy protocol, a high-risk arm

of a sole abnormality.

due to prednisone-poor response. A complete remission was con-

In our case protooncogene MYC, a critical component of leukemo-

rmed on the 15th and 33rd days of treatment, while minimal

genesis, could have been overexpressed due to both t(8;14)(q24;q11)

residual disease load of 2.09% and 0.11% was detected with eight-

translocation and PTEN alterations acting synergistically in a direct

color minimal residual disease assessed by ow cytometry (FC-

genomic and a posttranscriptional way, respectively.17 Translocation

MRD) at these time points, respectively. Before consolidation FC-

t(8;14)(q24;q11), which juxtaposes the TCR locus to the region

MRD load became undetectable, whereas the karyotype presented

of MYC, confers a strong proliferative advantage of MYC-rearranged

46,XY,t(8;14)(q24;q11)[12]/46,XY[11] and FISH analysis conrmed

subclones to be selected and expanded.4,5,10 This is reected in our

MYC rearrangement in 26% of examined cells. At the time of the second

patient, in whom this subclone, undetectable by the FC-MRD assay,

consolidation block, bone marrow relapse occurred with 65% blasts.

expanded by FISH from 5% at diagnosis to 26% before consolida-

Unlike at primary diagnosis, the late cortical T-ALL immunophenotype

tion and 100% at relapse. A complementary use of a real-time quan-

was revealed: cCD3+, CD7+, CD3+, CD2+, CD5+, CD4, CD8+/,

titative polymerase chain reaction method for MRD detection was

CD1a+, TdT, CD34, HLA DR, TCR/+, and TCR/. Cytoge-

unavailable in our patient; however it might also be inconclusive in

SKALSKA-SADOWSKA ET AL .

F I G U R E 2 Multiplex ligation dependent probe amplication (MLPA) analysis of bone marrow cells in T-ALL with t(8;14)(q24;q11.2) in a 4-yearold male. Deletions were dened as a sample/reference ratio <0.7 and are depicted as red dots; (A) at diagnosis and (B) at relapse. The last six
positions, in both panels (A) and (B), are genomic loci localized in X chromosome. The difference in the status of these loci between diagnosis and
relapse is due to the fact that female DNA was used as a reference for the sample at diagnosis (thus mimicking a heterozygous deletion) while male
DNA was used as a reference for the relapse sample

case of oligoclonality.18 La Starza et al. indicated a parallel case carry-

The genetic prole of our leukemia case with t(8;14)(q24;q11) and

ing TCR-MYC subclone of 60%, stratied as standard-risk T-ALL by

NOTCHwt /FBXW7wt /PTENmut agrees with that of leukemia-initiating

MRD, which relapsed resulting in therapeutic resistance.5

cells (LICs) in Pten-null experimental T-ALL model. LICs dened by

PTEN loss-of-function mutations result in MYC overexpression via

Pten inactivation followed by Tcr/-cMyc translocation proved to be

upregulation of the PI3K/AKT pathway and stabilized MYC protein

therapeutically resistant,20 and our case might be a clinical counter-

levels.17

The fact that diagnostic and relapse bone marrow samples

part of this experimental model. Biallelic CDKN2A deletion resulting in

of our patient shared some PTEN deletions, while a relapse sam-

P14ARF loss-of-function, downregulation of ARFMdm2p53 pathway

ple harbored a new mutation, also supports the hypothesis of sub-

represented an additional synergistic hit promoting MYC proliferative

clone selection and may indicate relapse from the preleukemic clone.19

advantage through escape from p53-dependent apoptosis.20 La Starza

SKALSKA-SADOWSKA ET AL .

et al. reported four t(8;14)(q24;q11)-positive T-ALL cases with known

PTEN status. Of two of them who shared the same set of genetic lesions
and late cortical immunophenotype with our patient; one relapsed with
unfavorable outcome and the other survived after nonstandard treatment. The remaining two patients from La Starzas report were PTENwt
and are in the group of aforementioned six long-time survivors after
t(8;14)(q24;q11)-T-ALL.5,14 This suggests that PTEN status, together
with t(8;14)(q24;q11) and additionally DKN2A/B status, rather than
t(8;14)(q24;q11) itself, might be related to dismal prognosis.
The notion that T-ALL carrying a Burkitt-like MYC translocation
requires chemotherapy regimen as in mature B-cell neoplasm treatment has been successfully implemented in two cases completing the
list of 28 t(8;14)(q24;q11)-T-ALL cases with a known outcome.14,15
Co-targeting the deregulated PI3K pathway and MYC, represents
another nonstandard therapeutic option requiring further studies.20
Our

presentation

contributes

to

scarce

observations

of

t(8;14)(q24;q11) as a candidate T-ALL prognostic factor, and provides an associated molecular prole integrated with known routes
of NOTCH-independent/MYC-mediated leukemogenesis. Prospective
screening for this genetic prole in T-ALL and large-scale clinical trials
are required to fully elucidate its prognostic value.

ACKNOWLEDGMENTS
The authors wish to acknowledge grants 2014/15/B/NZ2/03394 and
2013/11/N/NZ5/03730 to BS-Z from the National Science Centre
Poland. BS-Z was additionally supported by the EMBO short-term fellowship ASTF 502015. Additionally, the authors wish to acknowledge
Dr. . Sdek (Medical University of Silesia) for his contribution to cytometric immunophenotyping and E. Orlova for contribution to MLPA
analysis. We would like to thank Dr. B. Konatkowska who treated the
patient and Professor J. Wachowiak (Pozna University of Medical Sciences) for his strong support.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.

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