Impact de la biologie sur la prise en charge ... from very immature to more mature
precursors .... CM et al NEJM 2009. Doen Ber M et al Lancet Oncology 2009 ...
Impact de la biologie sur la prise en charge des LAL de l’enfant et de l’adolescent : une vue du clinicien
Robert Debré, Février 2013
Acute leukemias • Malignant process involving a lymphoid or myeloid marrow precursor cell Heterogeneous collection of diseases
• Associated to deregulation of fundamental processes: – proliferation – differentiation – senescence – apoptosis
Acquired genetic abnormalities
Acute lymphoblastic leukemia • Malignant tranformation of a cell which is a precursor of a lymphocyte B-lineage ALL (85%) or T-Lineage ALL (15%)
• Acquired genetic/epigenetics abnormalities – drive a differentiation blockade – leading to phenotypic variation from very immature to more mature precursors
More and more biology to:
• • • • •
Classify Stratify at the initial phase Stratify later on : early response evaluation Understand Innovate
Current outcomes in childhood and adolescent ALL: exemple of the FRALLE 2000 protocol
The patient, the disease, their interactions THE PATIENT
THE LEUKEMIC CELL
- known predisposed background : - e.g. Down syndrome - not known: - genetic polymorphisms e.g. drug metabolism variability
- morphology - immuno-phenotyping - classical and molecular cytogenetics - targeted molecular biology - global approaches: transcriptomics, CGH array, SNP, GW sequencing, epigenetics, protéomics
Interactions with stroma Neoangiogenesis Immune response
Contribution of cytomorphology and immuno-phenotyping • Cytology/ cytochemistry: – diagnosis – differentiate a rare form: L3 ALL: Burkitt’s leukemia • Immunophenotype (20-30 Mab): – diagnostic confirmation – discriminate BCP vs T-cell ALL – rare entities ex: pro-B ALL (CD10-) – can suggest a cytogenetic abnormality – can define tools for MRD detection
Cytogenetics and Molecular biology • Abnormalities (modal number, structure) (translocations+++) – Classical Karyotype (G/R banding) – FISH, chromosome painting
• RT(Q)-PCR detection of – Chimeric transcripts – Overexpression of a normal transcript
• Near future: CGH-array? SNPs? Exome seq? transcriptomics?
Molecular consequences of chromosomal abnormalities : modification of the expression of target genes Gene overexpression Normal : 2 alleles
Fusion gene alterations
*
Mutation : activating or inactivating Amplification Haplo-insuffisiency or Inactivation of the 2nd allele
ACTIVATION OF ONCOGENES INACTIVATION OF TUMOR SUPPRESSOR GENES
Complexity : more than one event + epigenetics!
11
Pui et al, J Clin Oncol 2010
Pui CH et al, Blood 2012
Cytogenetics, molecular cytogenetics and prognosis of B-lineage ALL SURVIVAL
BAD/ VERY BAD PROGNOSIS - t(9;22) / BCR-ABL - t(4;11) / MLL-AF4 / MLL-R - hypodiploidy < 44 chromosomes - iAMP21 - t(17;19) / E2A-HLF
(N # 10%) 20-30% (80%?) 30-40% 40% 50-70% 0-20%
GOOD / VERY GOOD PROGNOSIS (N # 50%) - hyperdiploidy > 50 chromosomes - t(1;19) / E2A-PBX1 - t(12;21)/TEL-AML1
85-90% 85-90% 90-95%
EFS by CYTOGENETICS: FRALLE 93
t(12;21) : t(1;19) : hyperdipl: t(4;11) : t(9;22) :
191 pts, 48 pts , 258 pts, 34 pts, 40 pts,
78+/-3% 85+/-5% 81+/-2% 27+/-7% (age>1 y : 13pts, 31+/-10%) 25+/-7%
EFS by CYTOGENETICS: FRALLE 2000
iAMP21: intrachromosomal amplification of chr. 21 • a non Standard-risk ALL (~2-3%) • diagnosed by FISH AML1 gene amplification: a novel finding in childhood ALL. Niini T, Kanerva J, Vettenranta K, Saarinen-Pihkala UM, Knuutila S. Helsinki, Finland. Haematologica 2000 Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Harewood L, Robinson H, Harris R, Al-Obaidi MJ, Jalali GR, Martineau M, Moorman AV, Sumption N, Richards S, Mitchell C, Harrison CJ. Southampton, UK. Leukemia 2003 Amplification of band q22 of chromosome 21, including AML1, in older children with acute lymphoblastic leukemia: an emerging molecular cytogenetic subgroup. Soulier J, Trakhtenbrot L, Najfeld V, Lipton JM, Mathew S, Avet-Loiseau H, De Braekeleer M, Salem S, Baruchel A, Raimondi SC, Raynaud SD Paris, France, Leukemia 2003 .
iAMP21 intrachromosomal amplification of CHR 21
Left: A metaphase showing an abnormal chromosome (whole chromosome paint 21) with multiple RUNX1 (red) and two normal TELsignals. Middle: A metaphase showing multiple RUNX1 exon signals (red) along the length of an abnormal chromosome 21 Right: Interphase cells showing clustering of the red RUNX1 and the two normal green ETV6 signals, using the LSI TEL-AML1 translocation probe (Vysis).
28 Children with iAMP21 out of 1386 Common/preB ALL in the UKALL 97/99 (2%)
(95%CI: 13%-48%)
5y OS : 71% (95% CI, 51%-84%)
Moorman AJ et al, Blood 2007
(EFS) and overall survival (OS) of 25 patients with iAMP21 (BFM Germany + Austria)
Attarbaschi A et al, J Clin Oncol 2008
FRALLE 93+2000 (2383 BCP-ALL pts): 24 pts with BCP-ALL and iAMP21
5 year EFS : 57±12% 5 year Overall Survival : 89±8%
International study iAMP21 • Ponte Di Legno Group • PI: C. Harrison • Ongoing
NEW TOOLS: CGH array,SNP arrays, sequence, transcriptomics,epigenetics, proteomics
• • • •
Molecular classification of acute leukemias New tools for detection Identification of resistance genes Identification of new metabolic pathways potential targets for targeted drugs
TRANSCRIPTOMICS
ALL vs AML Golub et al, Science 286:531, 1999
Yeoh E et al, Cancer Cell 2002
Armstrong SA et al Nature Genet 2002
Unsupervised hierarchy of 92 LAL-T
- Class prediction of known oncogenic groups: TAL, TLX1/HOX11 and TLX3/HOX11L2-related - Definition of new homogeneous oncogenic groups: TCRB-HOXA, TAL-RA and -RB, Immature. Soulier et al., Blood 2005 Hôpital Saint-Louis, Paris
Another achievement of gene expression profiling: a BCR-ABL like entity of ALL
• An entity with frequent IKZF1 del and bad prognosis Mullighan CM et al NEJM 2009 Doen Ber M et al Lancet Oncology 2009
Comparive Genomic Hybridization-array
PAX5
Nature May 2007
Mullighan CG et al, Nature 2007
IKZF1 deletion or sequence mutation and poor outcome in childhood Ph- ALL • deletion of IKZF1 (less commonly deleterious sequence mutations): 15-30% of BCP-ALL . • associated with an up to 3-fold increased risk of treatment failure in ALL . • multivariable analysis including age, sex, initial blood leukocyte count, and cytogenetic subtype: IKZF1 status independently associated with poor outcome.
Main Genetic alterations in BCP-ALL
Gene
Alteration
Frequency
pathway
clinical
PAX5
deletions translocations mutations
32%
TF B-cell diff
no
IKZF1
deletions mutations
15%
TF from HSC to BCP
Poor outcome Inc risk of ALL (SNP)
JAK1/2
mutations
18-35% DS-ALL JAK-STAT Constitutional 10% HR ALL activation
?
CRLF2
IGH@CRLF2 PR2Y8-CRLF2 overexpression
5-15% > 50% DS-ALL
Association with JAK mut and IKZF1 alteration
Poor outcome?
deletions mutations
19% rel ALL
Histone acetylation
Relapse++
CREBBP
80% BCR-ABL1 30% HR-ALL
14% HR ALL
GC resistance
An overflow of new abnormalities • B- Lineage ALL – – – –
IKZF1 deletion Overexpression of CRLF2 Mutation of JAK (1,2,3) CREBBP
• T-ALL – – – – –
NOTCH /FBXW7 CDKN2A/P16/ARF PTEN MYB PHF6
• …………….
HR-ALL : 187 cases/ sequence of 120 candidate genes
Zhang et al , Blood 2011
NCI high-risk B-Lineage ALL deletions of IKZF1 and mutations of JAK1,2,3
Mullighan CG et al, PNAS 2009
MINIMAL RESIDUAL DISEASE EVALUATION « HOW TO SEE WHAT YOU CANNOT SEE »
ALL and MRD : expectations of the clinicians • • • • •
Available for all patients Easy sampling ( blood > bone marrow) « Binary results » Quick results Cheap ...
TECHNIQUES IMMUNOPHENOTYPING Increasingly used But not today’s topic
MOLECULAR BIOLOGY - IG/TCR . Competitive PCR . RQ -PCR - FUSION TRANSCRIPTS . RQ-PCR
Comparison of MRD detection methods in ALL
Flow Cytometry
RT-PCR of fusion transcripts
PCR Ig/TCR rearrangements
Applicability (%)
Sensitivity
60-90(B) 90(T) 30-40(B) 30(T) 90
10-4 10-3_10-5 10-3-10-5
Risk of relapse at 3y Low MRD (< 10-4) at EOI
-4
>10 and < 10-2 at EOI High MRD (> 10-2) at EOI
EORTC I-BFM St-Jude 178 pts 242 pts 158 pts
# 9%
# 9%
5%
(88)
(104)
(123)
#17%
32%
24%
(30)
(38)
(33)
78%
72%
56%
(15)
(27)
(9)
Value of 2 time points for MRD- based stratification 129 pts, BFM protocols, 2 probes , S: 10-4 • Low risk (neg /neg) : 1 rel / 55 pts • High risk (>10-3/ >10-3) : 15 rel / 19 pts • Intermediate risk : 12 rel / 55 pts Van Dongen et al, Lancet 1998
3184 pts with BCP-ALL evaluable for MRD TP1 and TP2 in AIEOP-BFM 2000 By MRD (TP1 + TP2) SR 42% (18% of the events)
MR 52% (63% of the events)
HR 6% (19% of events)
3184 out of 4016 ph- BCP-ALL, by definition alive and in CR at TP2
Conter V et al, Blood 2010
464 pts with T-cell ALL evaluable for MRD TP1 and TP2 in AIEOP-BFM 2000 By MRD (TP1 + TP2) SR 16% (6.3% of the events)
MR 63% (50.5% of the events)
HR 21% (43.2% of events)
464 out of 627 pts with T-cell ALL, by definition alive and in CR at TP2
Schrappe M et al, Blood 2011
MRD: CONCLUSIONS • Decisional use of MRD to be done in controlled trials • Persisting problems: - sampling (nature, quality, heterogeneity, repetition) - techniques (sensitivity, reproducibility, quantification, probes) - not available for all patients - cost (++ if addition of techniques) - prediction of late and/or extra medullary relapse - prediction of events in MR patients
• New methods to come?
High–Throughput Sequencing detects MRD in T-cell ALL
Wu D et al, Sci Transl Med 2012
How to integrate a priori and a posteriori prognostic informations?
Integrated use of MRD classification and IKZF1 alt. accurately predicts 79% of relapses in pediatric ALL. • MRD and IKZF1 in 131 uniformly treated precursor-B-ALL patients
• Improvement of risk stratification by combining both? • Results • strong prognostic significance of MRD classification, independent of IKZF1 alterations • 8 / 11 relapsed cases in the large MRD-M group (n=81; 62%) :IKZF1 alteration+ • Integration of both MRD and IKZF1 status - resulted in a favorable outcome group (n=104; 5 relapses) and a poor outcome group (n=27; 19 relapses), - showed a stronger prognostic value than each of the 2 alone (hazard ratio (95%CI): 24.98 (8.29-75.31)). • MRD and IKZF1 status alone identified only 46 and 54% of the relapses, respectively.Their integrated use allowed prediction of 79% of all the relapses with 93% specificity. Nijmegen, The Netherlands.
Wanders E et al, Leukemia 2011
• 1061 B-linALL • POG 9905-06 • NCI SR: 562 • NCI HR: 499
Chen IM et al, Blood 2012
NCI HR: 2 remaining variables
Chen IM et al, Blood 2012
UNDERSTANDING ALL? • WHEN?
IN UTERO !
• HOW?
COMPLEX MULTISTEP PROCESS
• WHY?
GENE-ENVIRONNEMENT INTERACTION
Identification of fusion gene in neonatal blood spots of patients with TEL-AML1 leukemia.
The TEL-AML1 sequence is first determined by long range PCR, then oligonucleotide primers are designed for that unique sequence and for use in short range (conventional) PCR.
IN UTERO ORIGIN OF LEUKEMIA
Current knowledge and questions(1) 1. A potential oncogenic event has been demonstrated for : • Twins (MLL /R , TEL-AML1, T-ALL) • Non twins (R/MLL, TEL-AML1, RIgHBCP-ALL)
IN UTERO ORIGIN OF LEUKEMIA
questions(2) 2. Other oncogenic events ? Latency ++ (up to 14 years) Wiemels et al, Blood, 1999, 94, 1057
3. General phenomenon (ALL/AML)? AML1-ETO Wiemels et al, Blood, 2002, 99, 3801 4. Cord blood screening : < 1% positive for TEL-AML1 Mori et al, PNAS, 2002, 99, 8242
5. Environmental agents?
Whole-exome sequencing of pediatric acute lymphoblastic leukemia. • Sequencing of the whole exome of two cases of pediatric ALL carrying the ETV6/RUNX1 (TEL/AML1) fusion gene • 14 somatic mutations identified, including 4 and 7 proteinaltering nucleotide substitutions in each ALL. • 12 mutations (86%) occurred in genes previously described to be mutated in other types of cancer • 0 found to be recurrent in an extended series of 29 ETV6/RUNX1-positive ALLs. Lilliebjorn et al, Lund, Sweden, Leukemia 2011
Mullighan CG et al, Nature 2007
Topo-Isomerases II inhibitors • anticancer agents:
• • • •
VP-16, VM-26 Acridines, Anthracyclins ICRF 193
quinolones flavonoids catechins (tea, coca, wine) benzene metabolites, oestrogens
Genotoxic i.e. flavonoid
Illegitimate recombination of the MLL gene
Inherited Low NQO1function
INFANT LEUKEMIA
WHY? • No direct answer • Genome Wide Association Studies (GWAS) – IKZF1 – ARID5B (Hyperdiploidy ++) – CEBPE
• Clear associations, at a genome-wide threshold of 5 x10-7, between ALL and SNPs flanking the Ikaros family zinc finger 1 gene (IKZF1) in 7p12.2 (rs6964823, rs4132601, rs6944602 or rs11978267), and the AT-rich interactive domain 5b gene (ARID5B) in 10q21.2 (rs7073837, rs10740055, rs708942, or rs10821936, rs10994982). The association with ARID5B was more pronounced for hyperdiploid ALL than for other ALL in both GWAS. In the UK study, the SNP rs2239633 in the CCAAT/enhancerbinding protein epsilon gene (CEBPE) was also associated with ALL. Papaemmanuil et al, Nature Genet 2009 Trevino LR et al, Nature Genet 2009.
Why the relapse? • Clonal heterogeneity of ALL and origin of relapse – Same clone – Same clone with evolution – Different clone with common ancestor – Completely different ALL
Clonal selection in xenografted human T-cell ALL recapitulates gain of malignancy at relapse
Clappier E et al, J Exp Med 2011
Clappier E et al, J Exp Med 2011
Faderl et al. Blood,91:3995, 1998.
BCR-ABL
INHIBITION OF APOPTOSIS
CYTOPLASMIC LOCALISATION OF BCR / BCR-ABL
ACTIVATION OF THE RAS PATHWAY
ACTIVATION OF cMYC
Imatinib : mechanism of action
Goldman JM, Melo JV. N Engl J Med. 344:1084-1086.
Imatinib and childhood ALL with Philadelphia chromosome
3y EFS: 80.5 ± 11%
Shultz K et al, J Clin Oncol 2009
Minimum stratifying work-up proposal for ALL CLASSICAL CYTOGENETICS FISH TEL-AML1 • TEL-AML1 • High Hyperdiploidy • iAMP21 FISH MLL (only CD10 – or weak?) RT-PCR: MLL-AF4, BCR-ABL, E2A-PBX1 (TEL-AML1) MLPA: deletion of IKZF1 Ig/TCR rearrangements / LAPs : MRD tools To be discussed for research and specific therapeutic areas Transcripts for T-ALL ( including NUP214-ABL: glivec; also HR B-ALL?) Notch/FBXW7 ( gamma sec inhibitors) CRLF2 overexpression /JAK mut/STRN3-JAK2 ( JAK inhibitors) CGH/SNPs
Conclusions • Increased impact of a new biology of ALL (pb of cost and complexity) • To come : new classifications – Diagnosis – Prognosis – Therapeutics • To come hopefully : new drugs +++ – targeted ( Ab and small molecules) – proapoptotic – antiangiogenesis – differentiating agents – immunotherapy.
BACK-UP SLIDES
More targeted agents to come • JAK2 inhibitors • ……. • Antibodies – Anti CD19 – Anti CD22 +/- cytotoxic agent
Genetic alterations vs differentiation in B lineage ALL
Mullighan CG, Clin Cancer Research 2011
Conter V et al, Blood 2010
A) Relapse-free survival of the three MRD-based risk groups of children treated for ALL according to protocols of the International BFM Study Group. The three risk groups were defined by combined MRD information at the end of induction treatment and before consolidation treatment (B) Relapse-free survival according to the qualitative (presence or absence) and quantitative detection of MRD after the completion of induction therapy in EORTC trial 58881
Mullighan CG, Clin Cancer Research 2011
Childhood ALL and drug resistance Holleman et al, NEJM 2004
• • • •
271 children (173+ 98) MTT test for 4 drugs HU133 124 genes (known genes) and 28 cDNA PRED: 42 121 genes / 124 non classically VCR: 59 associated to ASPA: 54 resistance DNR: 22
Holleman, A. et al. N Engl J Med 2004;351:533-542
Holleman, A. et al. N Engl J Med 2004;351:533-542
LAL-T de l’adulte Chiarretti et al, Blood 2004
• 33 pts + un set indépendant de 18 pour RQ-PCR • HGU 95a • 34 gènes prédisent l ’échec d ’induction ( IL8 high, MX1 low, CD10 low) • 19 gènes prédisent la rechute dont 3 +++ (AHNAK high; CD2 low, TTK low) • mauvais : déficit de prolifération et d ’apoptose
Expression of 19 selected genes in T-ALL patients who relapsed versus those who remained in CCR
Chiaretti, S. et al. Blood 2004;103:2771-2778
Probability of maintaining CR for adult T-ALL
Chiaretti, S. et al. Blood 2004;103:2771-2778
Childhood B-lineage ALL and molecular response to treatment Cario G et al, Blood 2005
• 34 children (MRD HR: 18 SR :16) • BCP-ALL: index 1.0, no BCR-ABL / MLL-R/ TELAML1 • cDNA microarrays/ 30.000 genes • Bad : deficit of proliferation and apoptosis associated to some genes including TTK, MX1, FGR1 • standardisation of RNA preparation +++
Genes whose expression is associated with molecular treatment response
Cario, G. et al. Blood 2005;105:821-826
Ikaros plays a key role in tumor suppression in pediatric B-cell ALL and in particular in high-risk B-cell ALL (1). 1. Deletion of a single Ikzf1 allele or mutation of a single copy of Ikzf1 detected in 15% of all cases of pediatric Bcell ALL. 2. Resulted in haploinsufficiency of the Ikzf1 gene, along with expression of a functionally inactive form of Ikaros which could potentially act as a dominant negative form. 3. Deletion or mutation of a single copy of the Ikzf1 allele detected in over 80% of BCR-ABL1 ALL, associated with a poor outcome. 4. Haploinsufficiency of Ikzf1 associated with a three-fold increase in relapse of ALL following treatment.
Ikaros plays a key role in tumor suppression in pediatric B-cell ALL and in particular in high-risk B-cell ALL (2). 5. Expression profiles of BCR-ABL1 negative cases with haploinsufficiency of Ikzf1 and poor prognosis noted to have similar expression profiles to BCRABL1 positive ALL: definition of the BCR-ABL1-like subtype of B-cell ALL with haplo-insufficiency of Ikzf1 or other transcriptional regulators. 6. Inherited genetic variations of Ikzf1 : associated with the risk of childhood ALL 7. CRLF2 overexpression: significantly associated with JAK mutations and with deletions or mutations of Ikzf1. 8. Functional, leukemogenic significance of Ikzf1 haploinsufficiency and/or expression of dominant-negative Ikaros isoforms confirmed by several animal models. These models demonstrated that the expression of the dominant negative Ikzf1 allele in CD34+ cells results in impaired lymphoid differentiation.These models also demonstrate that the haploinsufficiency of Ikzf1 accelerates the development of leukemia in both retrovirally transduced bone marrow transplants and in a transgenic model of BCR-ABL1 ALL
Conclusion about IKAROS • Ikaros acts as a highly clinically-relevant tumor suppressor in B-cell ALL and particularly in highrisk B-cell ALL •A modest decrease in Ikaros activity (e.g. haploinsufficiency) is sufficient to contribute to leukemogenesis
Phosphorylation regulates the tumor suppressor function of Ikaros CK2 kinase directly phosphorylates and functionally inactivates Ikaros PP1 phosphatase counteracts this process. Functional inactivation of Ikaros by CK2 kinase promotes leukemogenesis.
CHROMOTHRIPSIS
Not considered today •
Routine but crucial biology of the induction phase: • • • •
•
biochemistry (e.g. tumor lysis syndrome, follow-up of pancreatic and liver function) coagulation (risk of DIC followed by a thrombophilic state) standard hematological follow-up (need for red cells or platelets transfusion) microbiology (infection)
Pharmacology (MTX) / pharmacogenetics (TPMT)
FRALLE 2000 (no infant, no Ph+ ALL) 3 groups SR-BCP ALL: A 1176 pts HR-BCP ALL: B 650 pts T-cell ALL: T 350 pts
(54%) (30%) (16%)
Current outcomes in childhood and adolescent ALL: exemple of the FRALLE 2000 protocol
Pui CH et al, NEJM 2009
UKALL MRC Last protocols
Immunoglobulin
IgH
IgL
membrane of the B lymphocyte
Rearrangement of the IgH gene by PCR VH germinal
D H
JH
Cµ µ
V-D-J Recombination rearranged
PCR
PCR mediated Junctional Amplification
Strategy for amplification of VH-DH-JH rearrangements VH FR1
FR1c
VH1 VH2 VH3 VH4 VH5 VH6
FR1f
CDR1
FR2 CDR2
FR2 +
DH FR3
FR3
CDR3
JH FR4
JH
Polyclonal
Population clonale
Population
PCR
PCR
+ électrophorèse Monoclonal Population
A story of treatment escalation VH3-JH49
Follow-up RUB. BE. 1.0E+00
1.0E-01
1.0E-02
Albumin 1.0E-03
1.0E-04 19/07/0118/08/0117/09/0117/10/0116/11/0116/12/01 %
13y, BCP-ALL, 45000 WBC, D8GPR,D21 M1
A story of treatment escalation
MRD
1
PT. Blood
10-1
HSCT
10-2
1991
BM
DLI
10-3 10-4 10-5
1
2
3
4
5
6
2y 7m, 20.000 WBC, BCR-ABL, Fralle 92, D21 M1
7
8
years
A story of treatment deescalation
Vδ1Jδ1 Vδ1Jδ1 Follow-up Bez. 1,00E+00 1,00E-01
Albumin
1,00E-02 1,00E-03 1,00E-04 1,00E-05 mars-02
avr-02
mai-02
juin-02
juil-02
12 y, T-ALL, 2300GB, complex karyotype, Fralle 2000, D8PPR, D21 M3
Yeoh et al, Cancer Cell, 2002, 1,133: Statistical methods !!!!!!! • • • • •
Hierarchical clustering Principal component analysis Discriminant analysis with variance Self organizing maps Algorithms : – K- nearest neighbors – Support vector machine – Collective likehood of emerging patterns – Artificial neuronal network – Weighted voting
Yeoh et al, Cancer Cell, 2002, 1,133: Results
• Subgroup Prediction – One gene: T-ALL (CD3D) E2A-PBX1(PBX1) – 7-20 genes : other subgroups • Prediction of relapses – T-ALL : 97% (7 genes) – > 50CHR : 100% (20 genes)
BUT TODAY???
• Prediction of secondary AMLs – TEL-AML1 : 100% (20 genes)-RSU1/ MSH3)
et al, Leukemia 2005
Impact of NOTCH/FBXW7
Ben Abdelali R et al, Blood 2011
• Yang JJ, Cheng C, Yang W, et al. Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 2009 • Kawedia JD, Kaste SC, Pei D, et al. Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood • Ellinghaus E, Stanulla M, Richter G, et al. Identification of germline susceptibility loci in etv6-runx1-rearranged childhood acute lymphoblastic leukemia. Leukemia • Chen SH, Pei D, Yang W, et al. Genetic variations in gria1 on chromosome 5q33 related to asparaginase hypersensitivity. Clin Pharmacol Ther 2010.
