New Genetic Abnormalities

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New Genetic Abnormalities and TreatmentResponse in Acute Lymphoblastic Leukemia

Jules P.P. Meijerink, Monique L. den Boer, and Rob Pieters

Numerous genetic abnormalities have been identified in acute lymphoblastic leukemia (ALL). Here we review the recurrent abnormalities with emphasis on those recently discovered, and discusstheir association with chemotherapy resistance or sensitivity and with clinical response to therapy.

Also, the role of genetic abnormalities in leukemogenesis and their potential as therapeutic targets will be discussed.Semin Hematol 46:16–23 © 2009 Elsevier Inc. All rights reserved.

B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

In general, children with B-lineage acute lympho-blastic leukemia (ALL) have a more favorable clini-cal outcome than those suffering from T-lineage

ALL. B-lineage ALL forms a heterogeneous group andharbors many underlying genetic lesions with variabletreatment responses ( Table 1 ).

Genotypes Currently Used for Risk-AdaptedStratification of Pediatric Precursor B-ALL

The two main genetic subtypes TEL-AML1–positiveand hyperdiploidy with greater than 50 chromosomestogether account for 50% of precursor B-ALL cases.

Both are associated with a favorable outcome, having a5-year disease-free survival (DFS) of greater than 85%.1

This favorable prognosis is most likely due to relativesensitivity of TEL-AML1 precursor B ALL to L-asparagi-nase,whereas hyperdiploid cases respond well to L-as-paraginase and antimetabolites like 6-mercaptopurineand methotrexate.2,3 Within the TEL-AML1–positive

subtype, prognosis is impaired in approximately 10% of the cases bearing two copies of the TEL-AML1–translo-cated gene, due to the high frequency of early relapsesand increased resistance to prednisolone.4

The unfavorable genetic subtypes BCR-ABL1–posi-

tive ALL and MLL-rearranged ALL each account for lessthan 5% of children with ALL who are older than 1 year of age. In contrast, the portion of MLL-rearranged ALL

is greater than 80% in infants up to 12 months of age.5

The dismal prognosis has been linked to resistance to

various drugs, L-asparaginase for BCR-ABL1–positive ALL and glucocorticoids and L-asparaginase for MLL-

rearranged ALL.6,7 Investigations have shown that well-

known resistance mechanisms found in (solid) cancers,

such as abnormalities in drug efflux systems (P-glycop-

rotein, multidrug resistance–associated protein, and

others), detoxifying systems (glutathione-linked), apo-

ptosis pathways, amino acid metabolism, and glucocor-ticoid receptor signaling are not the main explanations

for drug resistance in pediatric ALL.8,9 In contrast, ge-

nome-wide technologies have revealed new insights as

to the causes of resistance in pediatric ALL, and as a

consequence have opened a new era of potential resis-tance modifying agents, such as reversing glucocorti-

coid resistance by glycolysis inhibitors.10-12

The above-mentioned genetic abnormalities are

mutually exclusive, although incidentally combina-tions have been reported, such as hyperdiploidy and

TEL-AML1–positivity. These genotypes (with the ex-

ception of hyperdiploidy) result in fusion genes that

affect the self-renewal and differentiation capacity of

hematopoietic cells. Drugs that specifically target

fusion gene products and/or associated pathways are be-

ing developed and tested in clinical trials. Small-inhibitory

molecules such as imatinib (Gleevec/Glivec, Novartis)and dasatinib (Bristol-Myers Squibb) have relative speci-

ficity towards activated tyrosine kinases and may there-

fore effectively kill cells that have abnormalities in these

genes, as in BCR-ABL1–positive ALL.13,14

New Recurrent GeneticAbnormalities in Precursor B-ALL

The currently known genotypes used to stratify pa-

tients in risk-adapted treatment regimens only com-

prise about 60% of precursor B-ALL cases. The genetic

Department of Pediatric Oncology/Hematology, Erasmus Medical Center

Rotterdam–Sophia Children’s Hospital, Rotterdam, The Netherlands.

Address correspondence to Rob Pieters, MD, PhD, Department of Pedi-

atric Oncology/Hematology, Erasmus Medical Center Rotterdam–

Sophia Children’s Hospital, Dr Molewaterplein 60, 3015GJ Rotter-

dam, The Netherlands. E-mail: [email protected]

0037-1963/09/$ - see front matter

© 2009 Elsevier Inc. All rights reserved.

doi:10.1053/j.seminhematol.2008.09.006

Seminars in Hematology, Vol 46, No 1, January 2009, pp 16–2316



abnormalities in the remaining 40% are unknown, rare,or not mutually exclusive. Since the highest absolutenumber of relapses occurs within this remaining cate-

gory, progress in overall treatment results in pediatric ALL can only be obtained by the discovery of new genetic markers that can be used to identify thosepatients who are at high risk of treatment failure.15

Intrachromosomal Amplification of Chromosome 21

A small but prognostic highly unfavorable group, with a 5-year pDFS of less than 30%, harbors an in-trachromosomal amplification of chromosome 21(iAMP21).16 The iAMP21 includes additional copies of the AML1 gene and is found in about 2% of precursor

B-ALL cases. An additional copy of the AML1 gene islinked to a favorable outcome of TEL-AML1–positive

ALL cases, suggesting that the adverse prognosis iniAMP21 cases may not be due to increased activity of

AML1-responsive genes.4

Gene Mutations

Mutations in genes may affect the activity of corre-sponding proteins: activity may increase by mutationsthat alter the life-time, substrate specificity, bindingcapacity, or autoregulatory elements of the protein inquestion. In childhood precursor B-ALL activating mu-tations have been found in the Fms-like tyrosine kinase

receptor gene ( FLT3 ) in approximately 8% of cases,

especially MLL-rearranged and hyperdiploid ALL.17,18

This gene is involved in the early hematopoiesis by

activating signal transduction pathways involved in

proliferation and survival of progenitor cells. Mutationsin FLT3 have been shown to abolish the auto-inhibitory

capacity of the juxtamembrane domain ( FLT3-ITD mu-tation) or result in constitutive activity due to single

amino acid substitutions in the kinase domain ( FLT3-

835/836 mutations). In addition to mutations, a high

expression level of FLT3 has been linked to a poor prognosis of MLL-rearranged ALL in infants; the high

expression level itself was sufficient to result in phos-

phorylated (and hence activated) FLT3 receptor with-

out the need for activating mutations.19 Activated FLT3

has been shown to be a good target for newly devel-

oped small-molecule inhibitors that interfere with thecatalytic domain of the tyrosine kinase, abolishing the

further triggering of the downstream survival (AKT-

mediated) and proliferation (RAS/MAPK-mediated) sig-

naling cascades, such as the small-molecule inhibitorsPKC412 and CEP-701.20-22

Besides FLT3, mutations have also been found in

downstream effector genes of tyrosine kinase recep-

tors, such as the SHP-2 protein tyrosine phosphatase–

encoding gene PTPN11. This gene is mutated in about7% of precursor B-ALL cases, mainly common ALL cases

negative for the TEL-AML1 translocation. Mutations in

this gene are often mutually exclusive with other genes

that also affect the downstream RAS/MAPK signaling

Table 1. Summary of Genetic Lesions and Outcome in Pediatric Precursor B-ALL (older than 1 year)

Genetic Abnormality Rearrangement Gene(s)5-Year

DFS (%) Frequency (%)Therapeutic

Inhibitor

Known genotypeTEL-AML1 t(12;21)(p13;q22) TEL; AML1 80-85 20-25

Hyperdiploid Ͼ50 chromosomes 95-90 25E2A-PBX1 t(1;19)(q23;p13) E2A; PBX1 85 5BCR-ABL1 t(9;22)(q34;q11) BCR; ABL1 25-40 3-5 Imatinib/dasatinibMLL 11q23 MLL; various fusion

partnersϽ30 2

New recurrentabnormalities

Del9p del(9)(p21) CDKN2A/B 75 30-35 (40-45)1

Del9p del(9)(p21) PAX5 30-35 (40-45)1

iAMP21 ϩ21 or dup(21)(q22q22) AML1 29 2Dic(9;20) dic(9;20)(p11-13;q11) ND ND 2BCR-ABL1–like ND ND 60 15-20

MutationsFLT3 FLT3 Ͻ202 8 (15-20)3 PKC412/CEP-701SHP-2 PTPN11 ND 7

RAS/MAPK kRAS or nRAS ND 16-584 Farnesyl transferaseinhibitor

Abbreviation: ND, not determined.1Remaining group; negative for TEL-AML1, E2A-PBX1, BCR-ABL1, MLL-rearrangements and being non-hyperdiploid.2For MLL-rearranged or hyperdiploid pre-B-ALL.3For MLL-rearranged pre-B-ALL.4For hyperdiploid pre-B-ALL.

Genetic abnormalities and treatment response in ALL 17



pathway, such as mutations in NRAS and KRAS . These

RAS mutations have been observed at high (but vari-able) frequency in hyperdiploid precursor B-ALL andare hypothesized (but not yet proven) to be associated

with disease progression.23,24 FLT3, PTPN11, and RAS

mutations are mostly mutually exclusive and collec-

tively are present in about 35% of all precursor B-ALLcases. This high percentage of abnormalities impliesthat the FLT3-RAS signaling pathway should be further

explored as a potential target for novel inhibitory drugs.

Chromosome 9p Deletions

A relative large group of common/pre-B-ALL casesharbor deletions in chromosome 9p, including (among

others) the cell cycle–inhibitory CDKN2 locus encod-ing p16 INK4A and p15 INK4B and the B-cell transcription

factor PAX5 gene.25,26 However, these 9p deletions

were not restricted to the “remaining” group but were alsofound in BCRABL-positive, MLL-rearranged, TEL-AML1–

positive, and hyperdiploid cases. Chromosome 9p de-letions can vary between the loss of the entire 9pchromosomal region and regions of less than 50 kB in

size of all precursor B-ALL cases.26 Deletions of theCDKN2 locus at primary diagnosis did not affect theprognosis of common/pre-B cases, and involvement of

CDKN2 deletions in tumor progression is unlikely sincethe incidence of these deletions did not increase attime of relapse in paired initial-relapse samples.25

Abnormalities in TranscriptionFactors Involved in B-Cell Differentiation

PAX5 is a transcription factor involved in the com-mitment of hematopoietic cells to B-lineage differenti-

ation. PAX5 deletions and translocations [ PAX5-TEL asthe result of the t(9;12) and PAX5-ELN as the result of the t(7;9)] have been observed in 30% to 35% of pedi-atric precursor B-ALL cases.26 The prognosis of patientshaving leukemic cells with PAX5 fused to the Ets tran-scription factor TEL hypothetically may be inferior dueto blockade of B-cell differentiation, increased cellular

migration and homing, and a reduced apoptotic poten-

tial of affected cells.27

PAX5 deletions deregulate B-celldevelopment by a dominant negative loss-of-functionmechanism.28 The prognostic impact of both PAX5

translocations and PAX5 deletions is unclear in pediat-ric ALL. However, even if PAX5 abnormalities have noprognostic value, the affected genes and pathways still

represent highly interesting candidates for targetedtherapy, since the defect is leukemia-specific andpresent in a high percent of cases.

In addition to PAX5, a high frequency of abnormal-

ities in other transcription factors involved in B-celldifferentiation has been detected. Overall, about 40%of precursor B-ALL cases have deletions, amplifications,

mutations, or translocations in B-cell transcription fac-

tor genes that affect their function, including Ikaros,

E2A, EBF1, or PAX5.26,29 9p deletions were also found

in 84% of BCR-ABL1–positive ALL cases and highly

correlated with (partial) deletions of the B-cell tran-

scription factor Ikaros / IKZF1 on chromosome 7p.30 A

multi-step deficiency in the cell differentiation machin-

ery of precursor B-ALL is implicated, although thecausal relationship between 9p and 7p deletions re-

mains to be demonstrated.31

BCR-ABL1–like ALL

Recent gene expression profiling studies have iden-

tified a new subtype that includes 15% to 20% of all

precursor B-ALL cases and is associated with an unfa-

vorable outcome, with a 5-years pDFS of approximately

60%.32 The gene expression profile of these cases re-

sembles that of BCR-ABL1–positive patients, although

the latter are negative for this translocation; Addition-

ally, so-called BCR-ABL1–like cases are negative for other known genetic abnormalities, including TEL-

AML1, MLL-rearrangements, E2A-PBX1, and hyperdip-

loidy. Further characterization of this relative large un-

favorable prognostic group revealed greater than 70%

abnormalities in B-cell differentiation genes, including

PAX5, Ikaros, and EBF1, which is significantly higher

compared to 40% observed in the other common/pre-

B-ALL subgroups,26,29 further providing evidence that

the BCR-ABL1–like cases reflect a distinct entity.33

Some of these cases harbor a dicentric chromosome

dic(9;20), but this finding presumably can not explain

the unfavorable prognosis of BCR-ABL1–like cases,since limited data suggest that the prognosis of dic(9;

20)-positive cases is not worse compared to follow-up

data reported for other precursor B-ALL cases.15,34

It is intriguing that the newly discovered abnormal-

ities/deletions in B-cell transcription factors occur in

high frequency ( Ͼ40%), are often small in size and

found in restricted loci (focal deletions), affect normal

function by lack of expression or by generating domi-

nant (negative) isoforms, or dysregulate B-cell differen-

tiation similar to fusion genes such as TEL-AML1 and

BCR-ABL1. In general, the well-characterized geno-

types TEL-AML1, BCR-ABL1, MLL-fusion genes ( Ͼ50

partner genes), and E2A-PBX1 result in aberrant tran-

scription and differentiation factors affecting normal

hematopoiesis and cell fate. The recently discovered

abnormalities in B-cell transcription factors such as

PAX5 and Ikaros may point to a more general mecha-

nism underlying B-lineage leukemia, such as a disturbed

pre-B-cell receptor maturation machinery. The activity

and/or specificity of recombinase-activating RAG1/2

genes that are normally involved in rearranging V(D)J

segments as part of the B-cell receptor maturation pro-

cess may be altered in these leukemic cells. Recently,

RAG enzymes were postulated to be involved in pro-

ducing isoforms of B-cell transcription factors, as spe-

18 J.P.P. Meijerink, M.L. den Boer, and R. Pieters



cific recombination signal sequences (RSS) recognized

by RAG were found near deleted areas involving the Ikaros gene.30

T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

In contrast to childhood B-lineage ALL, for which

the general outcome has improved over the last de-cades to cure rates reaching nearly 85%, the prognosisfor children with T-ALL remains inferior: about 30% of these patients relapse following initiation of currenttreatment protocols.35

To date, many different types of genetic abnormali-ties have been identified in T-ALL, including chromo-somal translocations as consequence of erroneous T-cell receptor (TCR) rearrangements, non–TCR-driven

translocations, amplification, deletions, and point mu-

tations.36,37 Some of these abnormalities, which wedenote as “type A mutations,” occur in a mutually exclusive fashion and are responsible for arrest atspecific T-cell development stages (see Table 2 ).Based on gene expression profiling studies usingmicroarrays, growing evidence emerges that T-ALL

may comprise at least five distinct subgroups, each with a unique gene expression signature.38-40 The HOX11/ TLX1 and HOX11L2/TLX3 subgroups com-prise T-ALL cases with chromosomal translocationsaffecting the HOX11 or the HOX11L2 oncogenes,respectively. These two subgroups reflect distinctentities that may have opposing prognostic rele-

vance. The HOX11 subgroup has been associated with excellent prognosis,41,42 whereas HOX11L2-positive T-ALL in various studies has been associated

with a poor outcome.38,43,44

Table 2. Frequency of Molecular–Cytogenetic Aberrations in T-All, Relation to Outcome, and PotentialTherapeutic Targets

Type AMutations/

T-ALL Subgroups Rearrangement Gene(s) Outcome Frequency (%) Therapeutic Inhibitor

TAL/LMO t(1;14)(p32;q11)/t(1;7)(p32;q34) TAL1 Good? 15 HDAC inhibitor 1p32 deletion SIL/TAL1 Good? 4t(7;9)(q34;q32) TAL2 Unknown Ͻ1t(11;14)(p15;q11)/t(7;11)(q34;p15) LMO1 Unknown Ͻ1t(11;14)(p13;q11)/t(7;11)(q34;p13) LMO2 Unknown 711p13 deletions LMO2 Unknown 3

HOX11 t(10;14)(q24;q11)/t(7;10)(q34;q24) HOX11 Good 8HOX11L2 t(5;14)(q35;q32) HOX11L2 Poor 24

inv(7)p15q34)/t(7;7)(p15;q34) HOXA Undefined 5HOXA t(10;11)(p13;q14)

t(11;19)(q23;p13)9q34 deletions

CALM-AF10MLL-ENLSET-NUP214

Poor UnknownUnknown

4Ͻ1

3

Histone H3K79 methyltransferaseinhibitor

Unknown t(7;19)(q34;p13) LYL1 Unknown Ͻ1t(14;21)(q11.2;q22) BHLHB1 Unknown Ͻ1t(6;7)(q23;q34) MYB Unknown 3

Type B Mutations Rearrangement Gene(s) Outcome Frequency (%) Therapeutic Inhibitor

Cell cycle 9p21 deletions hypermethylation CDKN2A/2B CDKN2A/2B

Unknown 70 DNA methyltransferase inhibitor

t(7;12)(q34;p13)/t(12;14)(p13;q11) CCND2 Unknown Ͻ1NOTCH1 t(7;9)(q34;q34)

MutationsNOTCH1NOTCH1

UnknownGood

Ͻ1Ͼ50

␥ -secretase inhibitors

Mutations FBXW7 Good 9-30(pre)TCR t(1;7)(p34;q34) LCK Unknown Ͻ1 SRC kinase inhibitor

Mutations17q11.2 deletion

RAS NF1

UnknownUnknown

103

Farnesyltransferase inhibitor

10q23.31 deletion PTEN Unknown Ͻ1 PI3K/AKT inhibitorsMutations PTEN Unknown 17

Differentiation 6q23 duplication MYB Unknown 8-15Tyrosine kinases 9q34 amplification NUP214-

ABL1Poor 4 ABL kinase inhibitor

t(9;14)(q34;q32) EML1-ABL1 Unknown Ͻ1t(9;12)(q34;p13) ETV6-ABL1 Unknown Ͻ1t(9;22)(q34;q11) BCR-ABL1 Unknown Ͻ1t(9;12)(p24;p13) ETV6-JAK2 Unknown Ͻ1Mutations FLT3 No

impact3




Other subgroups, including the TAL/LMO and the

HOXA subgroups, may comprise various molecular–cytogenetic abnormalities affecting many different on-cogenes. The TAL/LMO subgroup includes T-ALL cases

with chromosomal aberrations affecting one of thehomologous basic helix-loop-helix genes (bHLH) TAL1

or TAL2, and/or one of the homologous LIM-domainonly (LMO) genes LMO1 or LMO2. These bHLH andLMO genes encode for cofactors that form a multifactor transcription complex, possibly explaining why these

abnormalities share a similar expression profile.37,40

The oncogenic role of this complex has been hypoth-esized to reflect inhibition of the E2A/HEB transcrip-tion factors.45 As transcriptional repression requiresrecruitment of histone deacetylases (HDACs), patients

with TAL/LMO abnormalities might benefit from theaddition of HDAC inhibitors to combination treatment.

Whether or not this subgroup has prognostic signifi-cance needs to be established.

The HOXA subgroup includes T-ALL cases with ab-errant activation of various members of the HOXA genecluster including HOXA9 and HOXA10.39,40,46 HOXA

activation can be due to rearrangements of the TCR␤

locus directly into the HOXA gene cluster due toan inversion or translocations on chromosome 7[Inv(7)(p15q34) or t(7;7)(p15;q34)],39,46 translocationsresulting in CALM-AF1039,47 or MLL fusion products,48

or due to a deletion on chromosome 9 [del(9)

(q34.11q34.13)] giving rise to a SET-NUP214 fusionproduct.40 The CALM-AF10 and the MLL and the SET-NUP214 fusion products bind in the promoter regions

of specific members of the HOXA gene cluster, andrecruit the histone H3-Lysine79 methyltransferasehDOT1L that promotes further epigenetic chromatinemodifications and HOXA genes activation.40,49,50 Pa-tients in this subgroup may therefore benefit fromhistone H3-K79 methyltransferase inhibitors. CALM-

AF10–positive T-ALL has been associated with a poor outcome,51,52 but further investigation is necessary tostudy whether this prognosis applies to the entire

HOXA subgroup.In contrast to type A mutations, type B mutations

are present in T-ALL irrespective of the T-ALL sub-

grouping (see Table 2 ). Type B abnormalities there-fore mirror common abnormalities and affect variouscellular processes, including cell cycle, T-cell com-mitment and self-renewal, TCR signaling processes,

or they result in the aberrant activation of tyrosinekinases.

In relation to loss of cell cycle regulators, the mostimportant abnormalities observed in T-ALL are homo-or heterozygous deletions of the cyclin-D/cyclin-depen-dent kinase-4 (CDK4) inhibitors p15/CDKN2B, p16/

CDKN2A in about 65% of pediatric T-ALL cases. The

CDKN2A locus also encodes for the alternative p14ARF

gene, which is part of the p53-regulated cell cycle and

apoptosis machinery. The true proportion may be un-

derestimated, as inactivation of these loci in T-ALL may occur from silencing, especially by promoter hyper-

methylation, which may provide a rationale for clinicalutlization of DNA methyltransferase inhibitors. Also,inactivation by point-mutations or post-transcriptionalmodifications has been described.53 Loss of p16 and/or

ARF in mouse models promoted T-cell leukemogene-sis,54 whereas reintroduction of these loci delayed on-cogenesis.55

The transmembrane receptor NOTCH1 is important

during hematopoiesis; it promotes self-renewal of stem-cells and T-lineage commitment of early lymphoid pro-genitor cells.56 For a long time, NOTCH1 has beenimplicated in T-ALL leukemogenesis due to its involve-ment in the rare translocation t(7;9).57 More recently,

NOTCH1 was found to be mutated in more than 50% of T-ALL cases. Mutations are located in the heterodimer-ization (HD) or adjacent juxtamembrane domains.Other mutations disrupt the C-terminal domain rich in

proline, glutamate, serine and threonine amino acidsalso denoted as the PEST domain, which normally func-tions as a target for the F-box protein FBXW7 as part of the E3-ubiquitin ligase complex that targets intracellu-lar NOTCH1 (ICN) for proteolytic degradation.58 PESTmutations can occur in combination with HD muta-tions. NOTCH1 mutations promote ligand-independentNOTCH1 cleavage by proteases such as ␥ -secretase,58,59

resulting in the release of ICN, which functions as a

transcription factor. Therefore, treatment of T-ALL us-ing ␥ -secretase inhibitors seemed promising. However,a phase I/II clinical study using ␥ -secretase inhibitors in

children with T-ALL has been unsuccessful to date, dueto low antitumor effectiveness and severe gastrointes-tinal toxicity.60

The FBXW7 gene is inactivated by mutations in 8%to 30% of T-ALL patients, occasionally in combination

with NOTCH1 HD mutations, and provides an alterna-

tive mechanism for NOTCH1 activation in T-ALL.61,62

The presence of NOTCH1 mutations and/or FBXW7

mutations has been correlated to good initial treatmentresponse and good outcome.63,64

During normal T-cell development, NOTCH1 is animportant transcription factor that activates a variety of

genes. NOTCH1 also controls the assembly of the pre-TCR complex during T-cell development by regulatingthe expression of the pre-TCR alpha gene ( pT ␣ ). For

various T-ALL oncogenes, a pivotal synergistic role for

this pre-TCR complex has been demonstrated in T-cellleukemogenesis. An important oncogenic role of thiscomplex was further supported by the finding of rear-rangements or (in)activating point mutations in directdownstream signaling components of this pathway, or in the closely associated RAS-MAPK and the PI3K-AKTpathways. These include aberrant expression of SRC -kinase LCK due to the t(1;7) translocation ( Ͻ1%),65

activating RAS mutations ( ϳ8%–10%),66 inactivating de-

letions/mutations of the RAS regulator NF1 ( ϳ3%),67 or




inactivating mutations of PTEN ( ϳ17%) resulting in

constitutive activation of the AKT survival pathway.68

These findings also may provide new rationales for experimental protocols to treat T-ALL with either SRC-kinase inhibitors, farnesyltransferase inhibitors, or PI3K-AKT inhibitors.

Finally, some mutations involve the formation of fusion products with potent tyrosine kinase activity.Several of these fusion products affect the tyrosinekinase domain of ABL1 due to rare translocations in-

cluding BCR-ABL1, EML1-ABL1, and ETV6-ABL1. The NUP214-ABL1 fusion product due to an extra chromo-somal amplification has been identified in about 6% of T-ALL cases. To date, this abnormality has predomi-nantly been identified in T-ALL subclones of the

HOX11L2, HOX11, and HOXA subgroups, suggestingthat it represents an important mechanism for diseaseprogression, as a relative late event in T-ALL that syn-ergizes with deregulated HOX genes.69 Activation of

the tyrosine kinase activity of FLT3 due to tandemduplications in the juxtamembrane domain have beenidentified in leukemic subclones in less than 3% of theT-ALL cases.70 Although NUP214-ABL or mutant FLT3

positive T-ALL may respond to potent tyrosine kinaseinhibitors, including imatinib69 or PKC412 (Novartis),such treatment may only be effective against theseleukemic subclones, leaving residual T-ALL cells fromthe original clone unaffected.

CONCLUSIONS

Genetic classification of ALL has already become very important for daily practice in treating children with ALL. In the last decade, the application of new genome-wide screening techniques, such as microar-

ray-based gene expression studies and array-compara-tive genomic hybridization (array-CGH) studies, haveled to the discovery of many new genetic abnormalitiesin childhood B- and T-lineage ALL. The exact functionalrole of these abnormalities in the development of ALLremains to be elucidated, as well as their roles asprognostic factors or as potential therapeutic targets.Knowledge gained from current and future studies willlead to a better diagnostic classification and to im-

proved patient-directed or individualized therapy for every child with ALL in the coming decades.

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