Acute lymphoblastic leukaemia (ALL) is a major paediatric cancer well-documented in Western countries [1]. Six decades ago, little to nothing was known about genetic factors being involved, especially in childhood ALL. However, thanks to many genetic studies including cytogenetic and molecular approaches, it has now been recognized that ALL consists of multiple subtypes, distinguishable by specific genetic lesion [2].
Down syndrome (DS) (trisomy 21) is a chromosomal disorder affecting 1 in 732 newborns in the United States [3]. DS children have 20–50 times enhanced rates of developing ALL (DS-ALL) compared to children without DS [4,5]; especially for the subtype B-cell precursor ALL (BCP-ALL) [6]. Survival of DS-ALL compared to ALL patients without constitutional trisomy 21 is very poor [6]. In many studies of DS-ALL cases, mutations in the
In hematopoietic disorders
Mutations in genes encountered in people with DS-ALL
Gene | Position of changes | References |
---|---|---|
JAK | V617F | [17] |
JAK | p.R683G | [19] |
JAK | p.R683K | [19] |
JAK1 | p.V658F | [12] |
JAK2 | p.T875N | [12] |
JAK2 | p.G861W | [12] |
GATA3 | c.778+1123T; c.779- 1748 | [24] |
PIP4K2A | c.678+761C>G | [24] |
MSH6 | p.T915A | [27] |
IL7R | p.S185C | [28] |
CRLF2 | p.F232C | [28] |
USP9X | p.F1115Lfs | [28] |
PAX5 | p.Gly186Ser | [30; 31] |
IKZF1 | p.Arg162Pro | [32] |
IKZF1 | p.His163Trp | [33] |
IKZF1 | p.Arg162Leu | [34] |
IKZF1 | p.Arg162Gln | [34] |
NBN | p.R162W | [34] |
NBN | p.K233Sfs*4 | [34] |
RTEL1 | p.R918W | [34] |
MLLT1 | p.R473Q | [34] |
FOXP1 | p.Q3Sfs*80 | [34] |
ERG | c.373+951A>G | [4; 5] |
CDKN2A | p.A148T | [37] |
ETV6 | p.A377T | [39] |
ETV6 | p.Y401N | [39] |
ETV6 | p.Pro214Leu | [40] |
ETV6 | p.Gln198* | [40] |
ETV6 | p.Leu379Pro | [40] |
NF1 | p.Val146Ile | [40] |
RUNX1 | p.Ile366_Gly367dup | [40] |
ASXL1 | p.Pro845Leu | [40] |
The gene
The
Putative functional germline variants in cancer-related genes (139 missense mutations; 3 frameshift deletions; and 1 splicing variant) were identified in 143 cases of ALL, especially the pathogenic variant p.Arg162Pro in
The
The
Besides the above-mentioned involvement of families with the
Liao and Liu [41] suggest that DS-ALL children’s treatment should be based on Dana Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols 00-001 (2000-2004) and 05-001 (2005-2011). Patients receive a multiagent remission induction consisting of weekly vincristine, prednisolone (40mg/m2/day for 28 days), L-asparaginase, and doxorubicin (total induction dose 60 mg/m2). In protocol 00-001, methotrexate (MTX) is administrated as a single high dose (iv 4g/m2) during induction; in protocol 05-001 MTX is administrated as a first low dose (40mg/m2) during first post induction phase, and after that as a second high dose (iv 5g/m2) during post induction phase [41].
Furthermore, Bohnstedt et al. [42] suggest treatment of patients according to protocols by the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL92 (1992-2001) or ALL2000 protocol (2003-2007). The four-week therapy consists of prednisolone, vincristine, doxorubicin and intrathecal MTX application, followed by asparaginase. The oral therapy starts with a single dose of 6-mercaptopurine (6-MP) and MTX of 75 mg/m2 per day and 20 mg/m2 per week [42]. The first-year therapy for patients with SR (standard risk)-ALL and IR (intermediate risk)-ALL, consists of (i) VCR (vincristin) and glucocorticosteroids or (ii) high -dose MTX 5 g/m2 /24h with intrathecal MTX and leucovorin. In ALL2000 protocol, the 6MP, the starting dose is 50 mg/m2 per day applying thiopurine methylansferase for thiopurine methyltransferase heterozygous patients, and for completely deficient patients 5-10 mg/m2 [42]. Buittenkamp et al. [43] based their treatment on the Dutch Childhood Oncology Group (DCOG) for ALL treatment protocol [43]. The DS-ALL patient got a reduced or high dose of MTX, varying from 10% to 75% of the maximum dose, and intensified by leucovorin. The DS-ALL patients registered in the European Organization for Research and Treatment of Cancer (EORTC 58951) protocol from 2002 received 0.5 g/m2 of MTX instead 5 g/m2. DS-ALL patients treated by the Pediatric Oncology Group (POG 9405) protocol started with 50% of total dose of daunorubicin, cytarabine, teniposide, histone decaetylase, and PEG-asparaginase; this type of therapy showed reduction of toxicity [43]. Chessells et al. [44] treated based on 2 consecutive United Kingdom protocols (MRC UKALL X and XI) for ALL, consisting of daunorubicin, prednisolone, vincristine, MTX, and L-asparginase [44]. This included introduction treatment ([week 1–4] with daunorubicin, and on days 1 and 2, prednisolone, vincristine, intrathecal methotrexate, L-asparaginase), first intensification ([week 5– 8] treatment with daunorubicin, vincristine, cytarabine, etoposide, and thioguanine for 5 days), CNS directed therapy ([week 9–12] treated with cranial irradiation 18Gy and intrathecal methotrexate), and continuing treatment ([week 13–104] daily mercaptopurine, weekly methotrexate, monthly prednisolone and vincristine) [44]. In a study by Dördelmann et al. [45] treatment was according to BFM (Berlin-Frankfurt-Munster) protocols. The patients with DS-ALL were treated with methotrexate (MTX) during consolidation and prophylactic cranial irradiation (CRT) [45]. Matloub et al. [46] and Whitlock et al. [47] treated their patients according to the Children’s Cancer Group (CCG) protocol involving cytarabine, vincristine, dexamethasone, pegaspargase and MTX. Matloub et al. [46] used 5 doses of vincristine and escalating IV methotrexate (MTX) without leucovorin rescue in the interim maintenance (IM) phase: this gave superior event free survival (EFS) when compared with 2 doses of vincistrine, oral (PO) MTX, PO mercaptopurine and dexamethasone [46].
Kroll et al. [57] analysed MTX–associated toxicity during treatment with MTX (5 g/m2) plus intrathecal MTX and 6-MP consolidation therapy in patients with DS-ALL and non-DS-ALL enrolled in an ALL-Berlin-Frankfurt-Muenster (ALL-BFM) trial between 1995–2016 and 1995– 2007. From 2004 onwards a dose of 0.5 g/m2 of MTX was recommended for DS patients as those had higher rates of toxicities after the first treatment with 5 g/m2 MTX compared with non-DS-ALL patients. Higher MTX doses to 1.0 g/m2 did not result in an increased rate of toxicities after the second course in DS-ALL patients [57].
Children with DS have increased incidence for BCP-ALL during the first years of life [48]; the reason for that is still unknown. It is accepted that the presence of a constitutive trisomy of chromosome 21 is sufficient to disturb foetal haematopoiesis [49]. Partial or complete gains of chromosome 21 are frequently seen in non-DS children B-ALL cases, but very rarely are seen in adult leukaemia [50,51,52]. The observation shows that trisomy of chromosome 21 may prime the hematopoietic system for cancer and that DS-associated leukaemia could be used to study paediatric leukaemia in general.
Several studies show that increased phenotypic diversity and changes in selection dynamics in the foetal liver and bone marrow may have a role in leukemic development in non-DS and DS children. Generally the mutation landscape of childhood leukaemia is different from adult leukaemia [52,53]. Cancer driver mutations found in DS-associated leukaemia are less frequently found in non-DS-associated leukaemia [19,35,54, 55, 56].
In conclusion, in-depth knowledge of the inherited and somatic genetic alterations in ALL has provided a compelling rationale to harness precision medicine opportunities for paediatric ALL, from refining molecular diagnosis, identifying new prognostic biomarkers, incorporating molecularly targeted therapies, and introducing genetic-guided dose adjustment. Implementing genetic counselling and cancer surveillance is also helpful in patients with inherited cancer susceptibility.
Therefore, precision oncologic diagnostics in paediatric ALL is a good example for illustrating the power of personalized medicine. During the next decades it is necessary to focus on the new challenges of precision medicine, and to establish a strategy to translate new genomic discoveries into therapy for children suffering from ALL. Implementation of NGS into clinical laboratory routine diagnostics and development of cost-effective diagnostic platforms to provide access for all patients at diagnosis will be paramount. Molecular therapy in all subtypes of ALL will require international collaborations to design prospective protocols and methods for cure. Efforts will be focused on investigating the mechanisms of TKI and combination strategies or immunotherapy and small-molecule inhibitors.