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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 discuss their 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
n general, children with B-lineage acute lymphoblastic leukemia (ALL) have a more favorable clinical outcome than those suffering from T-lineage ALL. B-lineage ALL forms a heterogeneous group and harbors many underlying genetic lesions with variable treatment responses (Table 1).
Genotypes Currently Used for Risk-Adapted Stratiﬁcation of Pediatric Precursor B-ALL
The two main genetic subtypes TEL-AML1–positive and hyperdiploidy with greater than 50 chromosomes together account for 50% of precursor B-ALL cases. Both are associated with a favorable outcome, having a 5-year disease-free survival (DFS) of greater than 85%.1 This favorable prognosis is most likely due to relative sensitivity of TEL-AML1 precursor B ALL to L-asparaginase,whereas hyperdiploid cases respond well to L-asparaginase and antimetabolites like 6-mercaptopurine and 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–translocated gene, due to the high frequency of early relapses and increased resistance to prednisolone.4 The unfavorable genetic subtypes BCR-ABL1–positive ALL and MLL-rearranged ALL each account for less than 5% of children with ALL who are older than 1 year of age. In contrast, the portion of MLL-rearranged ALL
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 Pediatric Oncology/Hematology, Erasmus Medical Center Rotterdam– Sophia Children’s Hospital, Dr Molewaterplein 60, 3015GJ Rotterdam, The Netherlands. E-mail: email@example.com 0037-1963/09/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2008.09.006
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 MLLrearranged ALL.6,7 Investigations have shown that wellknown resistance mechanisms found in (solid) cancers, such as abnormalities in drug efﬂux systems (P-glycoprotein, multidrug resistance–associated protein, and others), detoxifying systems (glutathione-linked), apoptosis pathways, amino acid metabolism, and glucocorticoid receptor signaling are not the main explanations for drug resistance in pediatric ALL.8,9 In contrast, genome-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 resistance modifying agents, such as reversing glucocorticoid resistance by glycolysis inhibitors.10-12 The above-mentioned genetic abnormalities are mutually exclusive, although incidentally combinations have been reported, such as hyperdiploidy and TEL-AML1–positivity. These genotypes (with the exception 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 being developed and tested in clinical trials. Small-inhibitory molecules such as imatinib (Gleevec/Glivec, Novartis) and dasatinib (Bristol-Myers Squibb) have relative speciﬁcity towards activated tyrosine kinases and may therefore effectively kill cells that have abnormalities in these genes, as in BCR-ABL1–positive ALL.13,14
New Recurrent Genetic Abnormalities in Precursor B-ALL
The currently known genotypes used to stratify patients in risk-adapted treatment regimens only comprise about 60% of precursor B-ALL cases. The genetic
Seminars in Hematology, Vol 46, No 1, January 2009, pp 16 –23
Mutations in FLT3 have been shown to abolish the auto-inhibitory capacity of the juxtamembrane domain (FLT3-ITD mutation) or result in constitutive activity due to single amino acid substitutions in the kinase domain (FLT3835/836 mutations). especially MLL-rearranged and hyperdiploid ALL. Mutations in this gene are often mutually exclusive with other genes that also affect the downstream RAS/MAPK signaling . substrate speciﬁcity.22)(q34. abolishing the further triggering of the downstream survival (AKTmediated) and proliferation (RAS/MAPK-mediated) signaling cascades. 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 those patients who are at high risk of treatment failure. such as the small-molecule inhibitors PKC412 and CEP-701. PBX1 BCR. mutations have also been found in downstream effector genes of tyrosine kinase receptors.16 The iAMP21 includes additional copies of the AML1 gene and is found in about 2% of precursor B-ALL cases. 1Remaining group. An additional copy of the AML1 gene is linked to a favorable outcome of TEL-AML1–positive ALL cases. This gene is mutated in about 7% of precursor B-ALL cases. In childhood precursor B-ALL activating mutations have been found in the Fms-like tyrosine kinase receptor gene (FLT3) in approximately 8% of cases.Genetic abnormalities and treatment response in ALL 17 Table 1.20-22 Besides FLT3.18 This gene is involved in the early hematopoiesis by activating signal transduction pathways involved in proliferation and survival of progenitor cells. E2A-PBX1. with a 5-year pDFS of less than 30%.15 Intrachromosomal Ampliﬁcation of Chromosome 21 A small but prognostic highly unfavorable group.20) BCR-ABL1–like Mutations FLT3 SHP-2 RAS/MAPK Rearrangement t(12. suggesting that the adverse prognosis in iAMP21 cases may not be due to increased activity of AML1-responsive genes. 2For MLL-rearranged or hyperdiploid pre-B-ALL. various fusion partners 5-Year DFS (%) 80-85 95-90 85 25-40 Ͻ30 Frequency (%) 20-25 25 5 3-5 2 Therapeutic Inhibitor Imatinib/dasatinib del(9)(p21) del(9)(p21) ϩ21 or dup(21)(q22q22) dic(9. Summary of Genetic Lesions and Outcome in Pediatric Precursor B-ALL (older than 1 year) Genetic Abnormality Known genotype TEL-AML1 Hyperdiploid E2A-PBX1 BCR-ABL1 MLL New recurrent abnormalities Del9p Del9p iAMP21 Dic(9.p13) t(9. not determined. abnormalities in the remaining 40% are unknown. mainly common ALL cases negative for the TEL-AML1 translocation. such as the SHP-2 protein tyrosine phosphatase– encoding gene PTPN11.q11) 11q23 Gene(s) TEL.q11) ND CDKN2A/B PAX5 AML1 ND ND FLT3 PTPN11 kRAS or nRAS 75 29 ND 60 Ͻ202 ND ND 30-35 (40-45)1 30-35 (40-45)1 2 2 15-20 8 (15-20)3 7 16-584 PKC412/CEP-701 Farnesyl transferase inhibitor Abbreviation: ND. the high expression level itself was sufﬁcient to result in phosphorylated (and hence activated) FLT3 receptor without the need for activating mutations. or autoregulatory elements of the protein in question.17. rare.19)(q23. In addition to mutations.20)(p11-13. Since the highest absolute number of relapses occurs within this remaining category.21)(p13. AML1 E2A. harbors an intrachromosomal ampliﬁcation of chromosome 21 (iAMP21). BCR-ABL1. 4For hyperdiploid pre-B-ALL. MLL-rearrangements and being non-hyperdiploid.4 Gene Mutations Mutations in genes may affect the activity of corresponding proteins: activity may increase by mutations that alter the life-time. 3For MLL-rearranged pre-B-ALL.19 Activated FLT3 has been shown to be a good target for newly developed small-molecule inhibitors that interfere with the catalytic domain of the tyrosine kinase. negative for TEL-AML1. or not mutually exclusive. a high expression level of FLT3 has been linked to a poor prognosis of MLL-rearranged ALL in infants. ABL1 MLL. binding capacity.q22) Ͼ50 chromosomes t(1.
26. about 40% of precursor B-ALL cases have deletions.33 Some of these cases harbor a dicentric chromosome dic(9. E2A-PBX1.P. PAX5 deletions and translocations [PAX5-TEL as the result of the t(9. these 9p deletions were not restricted to the “remaining” group but were also found in BCRABL-positive.26 The prognosis of patients having leukemic cells with PAX5 fused to the Ets transcription factor TEL hypothetically may be inferior due to blockade of B-cell differentiation. and involvement of CDKN2 deletions in tumor progression is unlikely since the incidence of these deletions did not increase at time of relapse in paired initial-relapse samples. In addition to PAX5.31 BCR-ABL1–like ALL Recent gene expression proﬁling studies have identiﬁed a new subtype that includes 15% to 20% of all precursor B-ALL cases and is associated with an unfavorable outcome. including TELAML1.12) and PAX5-ELN as the result of the t(7. Ikaros.25 Abnormalities in Transcription Factors Involved in B-Cell Differentiation PAX5 is a transcription factor involved in the commitment of hematopoietic cells to B-lineage differentiation.26 Deletions of the CDKN2 locus at primary diagnosis did not affect the prognosis of common/pre-B cases. even if PAX5 abnormalities have no prognostic value. and E2A-PBX1 result in aberrant transcription and differentiation factors affecting normal hematopoiesis and cell fate. or PAX5. and hyperdiploid cases. Overall. increased cellular migration and homing. E2A. M. 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 process may be altered in these leukemic cells. Recently. TEL-AML1– positive. MLL-rearranged.27 PAX5 deletions deregulate B-cell development by a dominant negative loss-of-function mechanism. Chromosome 9p deletions can vary between the loss of the entire 9p chromosomal region and regions of less than 50 kB in size of all precursor B-ALL cases. tor genes that affect their function. affect normal function by lack of expression or by generating dominant (negative) isoforms.26. Further characterization of this relative large unfavorable prognostic group revealed greater than 70% abnormalities in B-cell differentiation genes. since the defect is leukemia-speciﬁc and present in a high percent of cases. den Boer.34 It is intriguing that the newly discovered abnormalities/deletions in B-cell transcription factors occur in high frequency (Ͼ40%). including Ikaros. the well-characterized genotypes TEL-AML1. EBF1. Additionally. which is signiﬁcantly higher compared to 40% observed in the other common/preB-ALL subgroups. and R.32 The gene expression proﬁle of these cases resembles that of BCR-ABL1–positive patients. such as a disturbed pre-B-cell receptor maturation machinery.P.18 J.25. This high percentage of abnormalities implies that the FLT3-RAS signaling pathway should be further explored as a potential target for novel inhibitory drugs. and a reduced apoptotic potential of affected cells. and RAS mutations are mostly mutually exclusive and collectively are present in about 35% of all precursor B-ALL cases.24 FLT3. 20)-positive cases is not worse compared to follow-up data reported for other precursor B-ALL cases. and hyperdiploidy. These RAS mutations have been observed at high (but variable) frequency in hyperdiploid precursor B-ALL and are hypothesized (but not yet proven) to be associated with disease progression. or translocations in B-cell transcription fac- . a high frequency of abnormalities in other transcription factors involved in B-cell differentiation has been detected. MLL-fusion genes (Ͼ50 partner genes). BCR-ABL1. with a 5-years pDFS of approximately 60%. PTPN11. Pieters pathway. MLL-rearrangements. or dysregulate B-cell differentiation similar to fusion genes such as TEL-AML1 and BCR-ABL1. such as mutations in NRAS and KRAS. Meijerink. are often small in size and found in restricted loci (focal deletions). including PAX5. but this ﬁnding presumably can not explain the unfavorable prognosis of BCR-ABL1–like cases. and EBF1. ampliﬁcations.23.30 A multi-step deﬁciency in the cell differentiation machinery of precursor B-ALL is implicated. mutations. In general. The recently discovered abnormalities in B-cell transcription factors such as PAX5 and Ikaros may point to a more general mechanism underlying B-lineage leukemia.26 However.15.29 9p deletions were also found in 84% of BCR-ABL1–positive ALL cases and highly correlated with (partial) deletions of the B-cell transcription factor Ikaros/IKZF1 on chromosome 7p.9)] have been observed in 30% to 35% of pediatric precursor B-ALL cases. However. including (among others) the cell cycle–inhibitory CDKN2 locus encoding p16INK4A and p15INK4B and the B-cell transcription factor PAX5 gene. as spe- Chromosome 9p Deletions A relative large group of common/pre-B-ALL cases harbor deletions in chromosome 9p.20).L. although the causal relationship between 9p and 7p deletions remains to be demonstrated.28 The prognostic impact of both PAX5 translocations and PAX5 deletions is unclear in pediatric ALL. the affected genes and pathways still represent highly interesting candidates for targeted therapy. since limited data suggest that the prognosis of dic(9.29 further providing evidence that the BCR-ABL1–like cases reﬂect a distinct entity. RAG enzymes were postulated to be involved in producing isoforms of B-cell transcription factors. so-called BCR-ABL1–like cases are negative for other known genetic abnormalities. although the latter are negative for this translocation.
14)(q35. many different types of genetic abnormalities have been identiﬁed in T-ALL. growing evidence emerges that T-ALL may comprise at least ﬁve distinct subgroups.41.7)(p15.q32) EML1-ABL1 t(9.Genetic abnormalities and treatment response in ALL 19 ciﬁc recombination signal sequences (RSS) recognized by RAG were found near deleted areas involving the Ikaros gene.q34) Rearrangement 9p21 deletions hypermethylation Gene(s) TAL1 SIL/TAL1 TAL2 LMO1 LMO2 LMO2 HOX11 HOX11L2 HOXA CALM-AF10 MLL-ENL SET-NUP214 LYL1 BHLHB1 MYB Gene(s) Outcome Frequency (%) Good? Good? Unknown Unknown Unknown Unknown Good Poor Undeﬁned Poor Unknown Unknown Unknown Unknown Unknown 15 4 Ͻ1 Ͻ1 7 3 8 24 5 4 Ͻ1 3 Ͻ1 Ͻ1 3 Therapeutic Inhibitor HDAC inhibitor HOX11 HOX11L2 HOXA Histone H3K79 methyltransferase inhibitor Unknown Type B Mutations Cell cycle Outcome Frequency (%) Unknown Unknown Unknown Good Good Unknown Unknown Unknown Unknown Unknown Unknown Poor Unknown Unknown Unknown Unknown No impact 70 Ͻ1 Ͻ1 Ͼ50 9-30 Ͻ1 10 3 Ͻ1 17 8-15 4 Ͻ1 Ͻ1 Ͻ1 Ͻ1 3 Therapeutic Inhibitor DNA methyltransferase inhibitor NOTCH1 (pre)TCR Differentiation Tyrosine kinases CDKN2A/2B CDKN2A/2B t(7.p13)/t(12.19)(q23.q11)/t(7. and point mu- tations. non–TCR-driven translocations.q24) t(5.14)(p15.p13) 11p13 deletions t(10.7)(q23. Relation to Outcome.14)(q34.14)(p13.q34) NOTCH1 Mutations NOTCH1 Mutations FBXW7 t(1.44 Table 2.42 whereas HOX11L2positive T-ALL in various studies has been associated with a poor outcome.p13) t(14. the prognosis for children with T-ALL remains inferior: about 30% of these patients relapse following initiation of current treatment protocols.38-40 The HOX11/TLX1 and HOX11L2/TLX3 subgroups comprise T-ALL cases with chromosomal translocations affecting the HOX11 or the HOX11L2 oncogenes.q32) t(11.14)(p13. which we denote as “type A mutations.” occur in a mutually exclusive fashion and are responsible for arrest at speciﬁc T-cell development stages (see Table 2). Based on gene expression proﬁling studies using microarrays.11)(q34.q34) LCK Mutations RAS 17q11. for which the general outcome has improved over the last decades to cure rates reaching nearly 85%.2 deletion NF1 10q23.q11) CCND2 t(7.q22) t(6. deletions.p13) 9q34 deletions t(7.2.11)(q34.12)(q34.p13) ETV6-ABL1 t(9.p15) t(11.22)(q34.q11)/t(7.12)(p24.p13) ETV6-JAK2 Mutations FLT3 ␥-secretase inhibitors SRC kinase inhibitor Farnesyltransferase inhibitor PI3K/AKT inhibitors ABL kinase inhibitor .37 Some of these abnormalities.19)(q34. and Potential Therapeutic Targets Type A Mutations/ T-ALL Subgroups TAL/LMO Rearrangement t(1.q11) BCR-ABL1 t(9.14)(q24.38.35 To date.q34) 1p32 deletion t(7.12)(q34.q34) t(10.43.9)(q34.q11)/t(1. The HOX11 subgroup has been associated with excellent prognosis.7)(p32.q32) inv(7)p15q34)/t(7.31 deletion PTEN Mutations PTEN 6q23 duplication MYB 9q34 ampliﬁcation NUP214ABL1 t(9.30 T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA In contrast to childhood B-lineage ALL.36. Frequency of Molecular–Cytogenetic Aberrations in T-All.10)(q34.11)(p13. each with a unique gene expression signature.21)(q11. These two subgroups reﬂect distinct entities that may have opposing prognostic relevance.9)(q34. including chromosomal translocations as consequence of erroneous Tcell receptor (TCR) rearrangements.q14) t(11. ampliﬁcation. respectively.q11)/t(7.14)(p32.7)(p34.
or they result in the aberrant activation of tyrosine kinases.40 The oncogenic role of this complex has been hypothesized to reﬂect inhibition of the E2A/HEB transcription factors. TCR signaling processes.q34)]. treatment of T-ALL using ␥-secretase inhibitors seemed promising.50 Patients in this subgroup may therefore beneﬁt from histone H3-K79 methyltransferase inhibitors. and/or one of the homologous LIM-domain only (LMO) genes LMO1 or LMO2.39. NOTCH1 also controls the assembly of the preTCR complex during T-cell development by regulating the expression of the pre-TCR alpha gene (pT␣). However. which functions as a transcription factor.49.64 During normal T-cell development. M. den Boer.67 or .13)] giving rise to a SET-NUP214 fusion product.62 The presence of NOTCH1 mutations and/or FBXW7 mutations has been correlated to good initial treatment response and good outcome. a phase I/II clinical study using ␥-secretase inhibitors in children with T-ALL has been unsuccessful to date. p16/ CDKN2A in about 65% of pediatric T-ALL cases.45 As transcriptional repression requires recruitment of histone deacetylases (HDACs). Mutations are located in the heterodimerization (HD) or adjacent juxtamembrane domains.7)(p15. especially by promoter hypermethylation. Meijerink. which may provide a rationale for clinical utlization of DNA methyltransferase inhibitors.46 HOXA activation can be due to rearrangements of the TCR␤ locus directly into the HOXA gene cluster due to an inversion or translocations on chromosome 7 [Inv(7)(p15q34) or t(7. The HOXA subgroup includes T-ALL cases with aberrant activation of various members of the HOXA gene cluster including HOXA9 and HOXA10. and recruit the histone H3-Lysine79 methyltransferase hDOT1L that promotes further epigenetic chromatine modiﬁcations and HOXA genes activation. Also.60 The FBXW7 gene is inactivated by mutations in 8% to 30% of T-ALL patients.40.54 whereas reintroduction of these loci delayed oncogenesis. including cell cycle. serine and threonine amino acids also denoted as the PEST domain.46 translocations resulting in CALM-AF1039. occasionally in combination with NOTCH1 HD mutations. glutamate. it promotes self-renewal of stemcells and T-lineage commitment of early lymphoid progenitor cells. due to low antitumor effectiveness and severe gastrointestinal toxicity. NOTCH1 mutations promote ligand-independent NOTCH1 cleavage by proteases such as ␥-secretase. NOTCH1 was found to be mutated in more than 50% of T-ALL cases. Therefore.47 or MLL fusion products. CALMAF10–positive T-ALL has been associated with a poor outcome. which normally functions as a target for the F-box protein FBXW7 as part of the E3-ubiquitin ligase complex that targets intracellular NOTCH1 (ICN) for proteolytic degradation. The TAL/LMO subgroup includes T-ALL cases with chromosomal aberrations affecting one of the homologous basic helix-loop-helix genes (bHLH) TAL1 or TAL2. including the TAL/LMO and the HOXA subgroups.57 More recently. For various T-ALL oncogenes.52 but further investigation is necessary to study whether this prognosis applies to the entire HOXA subgroup. NOTCH1 is an important transcription factor that activates a variety of genes. NOTCH1 has been implicated in T-ALL leukemogenesis due to its involvement in the rare translocation t(7. Other mutations disrupt the C-terminal domain rich in proline. type B mutations are present in T-ALL irrespective of the T-ALL subgrouping (see Table 2). a pivotal synergistic role for this pre-TCR complex has been demonstrated in T-cell leukemogenesis. The CDKN2A locus also encodes for the alternative p14ARF gene. patients with TAL/LMO abnormalities might beneﬁt from the addition of HDAC inhibitors to combination treatment.66 inactivating deletions/mutations of the RAS regulator NF1 (ϳ3%). which is part of the p53-regulated cell cycle and apoptosis machinery.63.61. These bHLH and LMO genes encode for cofactors that form a multifactor transcription complex.7) translocation (Ͻ1%).P. the most important abnormalities observed in T-ALL are homoor heterozygous deletions of the cyclin-D/cyclin-dependent kinase-4 (CDK4) inhibitors p15/CDKN2B. Whether or not this subgroup has prognostic signiﬁcance needs to be established.39.58. Type B abnormalities therefore mirror common abnormalities and affect various cellular processes. In relation to loss of cell cycle regulators. possibly explaining why these abnormalities share a similar expression proﬁle.40.58 PEST mutations can occur in combination with HD mutations.48 or due to a deletion on chromosome 9 [del(9) (q34.59 resulting in the release of ICN.L.51. T-cell commitment and self-renewal. The true proportion may be un- derestimated.20 J.40 The CALM-AF10 and the MLL and the SETNUP214 fusion products bind in the promoter regions of speciﬁc members of the HOXA gene cluster. as inactivation of these loci in T-ALL may occur from silencing.37. inactivation by point-mutations or post-transcriptional modiﬁcations has been described. and provides an alternative mechanism for NOTCH1 activation in T-ALL.55 The transmembrane receptor NOTCH1 is important during hematopoiesis. or in the closely associated RAS-MAPK and the PI3K-AKT pathways. An important oncogenic role of this complex was further supported by the ﬁnding of rearrangements or (in)activating point mutations in direct downstream signaling components of this pathway. These include aberrant expression of SRCkinase LCK due to the t(1. may comprise various molecular– cytogenetic abnormalities affecting many different oncogenes. Pieters Other subgroups.65 activating RAS mutations (ϳ8%–10%).53 Loss of p16 and/or ARF in mouse models promoted T-cell leukemogenesis.9). In contrast to type A mutations.56 For a long time.11q34.P. and R.
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