JAK mutations in high-risk childhood acute
Charles G. Mullighana,1, Jinghui Zhangb,1, Richard C. Harveyc,1, J. Racquel Collins-Underwooda, Brenda A. Schulmand,
Letha A. Phillipsa, Sarah K. Tasiane, Mignon L. Lohe, Xiaoping Sua, Wei Liuf, Meenakshi Devidasg, Susan R. Atlasc,h,
I-Ming Chenc, Robert J. Cliffordi, Daniela S. Gerhardj, William L. Carrollk, Gregory H. Reamanl, Malcolm Smithm,
James R. Downinga,2,3, Stephen P. Hungern,2,3, and Cheryl L. Willmanc,2,3
Departments ofaPathology andfBiostatistics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;bCenter for Biomedical
Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Room 6071, 2115 East Jefferson Road, Rockville, MD
20852;cUniversity of New Mexico Cancer Research and Treatment Center, University of New Mexico Cancer Research Facility, University of New Mexico,
2325 Camino de Salud Northeast, Room G03, MSC08 4630 1, Albuquerque, NM 87131;dStructural Biology Department and Howard Hughes Medical
Institute, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105;eDepartment of Pediatrics, University of California, 505
Parnassus Avenue, San Francisco, CA 94143;gChildren’s Oncology Group, Department of Epidemiology and Health Policy Research, University of Florida
College of Medicine, 104 North Main Street, Suite 600, Gainesville, FL 32601;hPhysics and Astronomy Department, University of New Mexico, 800 Yale
Boulevard Northeast, Albuquerque, NM 87131;iLaboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
20852;jOffice of Cancer Genomics, National Cancer Institute, National Institutes of Health, 31 Center Drive 10A07, Bethesda, MD 20852;kNew York
University Cancer Institute, New York, NY 10016;lSchool of Medicine and Health Sciences, The George Washington University, 4600 East West Highway,
Suite 600, Bethesda, MD 20814;mCancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, 6130 Executive Boulevard,
Room 7025, Bethesda, MD 20852; andnSection of Pediatric Hematology/Oncology/Bone Marrow Transplantation and Center for Cancer and Blood
Disorders, University of Colorado Denver School of Medicine, 13123 East 16th Avenue, B115, Aurora, CO 80045
Edited by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, and approved April 10, 2009 (received for review November 19, 2008)
Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous
disease consisting of distinct clinical and biological subtypes that
are characterized by specific chromosomal abnormalities or gene
mutations. Mutation of genes encoding tyrosine kinases is uncom-
mon in ALL, with the exception of Philadelphia chromosome-
positive ALL, where the t(9,22)(q34;q11) translocation encodes the
constitutively active BCR-ABL1 tyrosine kinase. We recently iden-
tified a poor prognostic subgroup of pediatric BCR-ABL1-negative
ALL patients characterized by deletion of IKZF1 (encoding the
lymphoid transcription factor IKAROS) and a gene expression
signature similar to BCR-ABL1-positive ALL, raising the possibility
of activated tyrosine kinase signaling within this leukemia sub-
type. Here, we report activating mutations in the Janus kinases
JAK1 (n ? 3), JAK2 (n ? 16), and JAK3 (n ? 1) in 20 (10.7%) of 187
BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and
JAK2 mutations involved highly conserved residues in the kinase
and pseudokinase domains and resulted in constitutive JAK-STAT
activation and growth factor independence of Ba/F3-EpoR cells.
The presence of JAK mutations was significantly associated with
alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of
cases with JAK2 mutations; P ? 0.001) and deletion of CDKN2A/B
(70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases).
The JAK-mutated cases had a gene expression signature similar to
BCR-ABL1 pediatric ALL, and they had a poor outcome. These
therapeutic intervention in JAK mutated ALL.
IKAROS ? kinase ? mutation
ALL remains the second leading cause of cancer death in
children. To improve outcome, it is necessary to identify high-
risk patients at the time of diagnosis and then tailor therapy
toward the genetic lesions driving their leukemia.
Recent genome-wide analyses have identified common ge-
netic alterations in childhood ALL that contribute to leukemo-
genesis (2, 3). To identify genetic lesions predictive of poor
outcome in childhood ALL, we recently performed genome-
wide analysis of DNA copy number alterations, transcriptional
profiling, and gene resequencing in a cohort of 221 children with
B progenitor ALL predicted to be at high risk for relapse based
on age and presentation leukocyte count (4). These patients
were treated on the Children’s Oncology Group P9906 trial by
cute lymphoblastic leukemia (ALL) is the most common
pediatric cancer, and despite high overall cure rates (1),
using an augmented reinduction/reconsolidation strategy (‘‘Ber-
lin–Frankfurt–Mu ¨nster’’ regimen) (5, 6). This cohort excluded
patients with known good (ETV6-RUNX1 or trisomies 4 and 10)
or very poor (hypodiploid, BCR-ABL1) risk sentinel genetic
lesions, and it represents ?12% of noninfant B precursor ALL
cases (Table S1). Alteration of the lymphoid transcription factor
IKZF1 (IKAROS) was associated with poor outcome and a
leukemic cell gene expression signature highly similar to that of
BCR-ABL1 pediatric ALL (4). Furthermore, hierarchical clus-
tering of gene expression profiling data identified a subset of 24
cases with poor outcome (4-year incidence of relapse, death, or
second malignancy: 79.1%; 95% C.I., 58.6–99.6%) and expres-
sion of outlier genes similar to those seen in BCR-ABL1 ALL.
Together, these observations suggested that the poor-outcome,
IKZF1-deleted, BCR-ABL1-negative cases might harbor activat-
ing tyrosine kinase mutations. The JAK-STAT pathway may
mediate BCR-ABL1 signaling and transformation (7, 8), and
JAK1 and JAK2 are mutated in myeloproliferative diseases (9),
Down syndrome-associated ALL (DS-ALL), and T lineage ALL
(10–12). Here, we have performed genomic resequencing of
JAK1, JAK2, JAK3, and TYK2 in 187 diagnostic samples from this
high risk B-progenitor ALL cohort that had available DNA and
gene expression profiling data. This identified mutations in
JAK1, JAK2, and JAK3 in 20 patients (10.7%). The JAK-mutated
cases had a high frequency of concomitant deletion of IKZF1
(IKAROS) and CDKN2A/B, a gene expression profile similar to
BCR-ABL1 ALL, and extremely poor outcome.
JAK1, JAK2, and JAK3 Mutations in High-Risk Pediatric ALL. Genomic
resequencing of JAK1, JAK2, JAK3, and TYK was performed for
designed research; C.G.M., J.Z., R.C.H., J.R.C.-U., L.A.P., S.K.T., M.L.L., X.S., S.R.A., I.-M.C.,
X.S., and R.J.C. contributed new reagents/analytic tools; C.G.M., J.Z., B.A.S., L.A.P., S.K.T.,
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1C.G.M., J.Z., and R.C.H. contributed equally to this work.
2J.R.D., S.P.H., and C.L.W. contributed equally to this work.
3To whom correspondence may be addressed. E-mail: email@example.com,
firstname.lastname@example.org, or email@example.com.
This article contains supporting information online at www.pnas.org/cgi/content/full/
June 9, 2009 ?
vol. 106 ?
187 cases in the P9906 cohort that had available DNA, single-
nucleotide polymorphism array, and gene expression profiling
data. This identified 20 pediatric ALL patients (10.7%) with 20
heterozygous, somatic mutations of JAK1, JAK2, and JAK3 (Fig.
1, Tables S2 and S3, and Fig. S1). All patients with JAK
mutations lacked known common chromosomal translocations.
A total of 16 cases had JAK2 mutations, with 13 located in the
pseudokinase domain (R683G, n ? 10; R683S, n ? 1; I682F, n ?
D873N, and P933R). Three previously undescribed missense or
in-frame deletion mutations were also identified in the pseudoki-
nase domain of JAK1 (L624?R629?W, S646F, and V658F), as well
as a single JAK3 mutation, S789P. A total of 2 of the 9 DS-ALL
cases in our cohort harbored JAK2 mutations (QGinsR683 and
R683G), with the remaining 18 JAK mutations occurring in non-
DS-ALL patients (Tables S2 and S3). With the exception of JAK3
S789P, each mutation was located in highly conserved residues in
V617F mutation common in myeloproliferative disease) (13–16)
results in cytokine-independent in vitro growth of Ba/F3-Epo-R or
Ba/F3 cells (10, 11, 17).
Concomitant Genomic Abnormalities in JAK-Mutated ALL. The pres-
ence of JAK mutations in this cohort was significantly associated
with alterations of IKZF1 and CDKN2A/CDKN2B (Table S2).
IKZF1 deletions or mutations were present in 14 (70%) JAK-
mutated cases (and in 14 of 16 cases with JAK2 mutations) but
in only 25.7% of cases that lacked a JAK mutation (P ? 0.0001).
JAK mutations were also associated with CDKN2A/B deletion
(70% vs. 47%, P ? 0.06). An increased frequency of copy
number alterations at or flanking the IL3RA/CSF2RA/CRLF2
locus at the pseudoautosomal region of Xp22.3/Yp11.3 was also
observed in JAK-mutated cases (45.0% vs. 4.2%; P ? 0.0001). A
trend to a significantly higher presenting leukocyte count in
JAK-mutated cases was observed (158 ? 109/L vs. 101 ? 109/L;
P ? 0.06), but there was no difference in age of presentation.
Structural Modeling of JAK Mutations. The JAK pseudokinase
domain is thought to negatively regulate activity of the kinase
domain (18) and may mediate protein–protein interactions
(19–21). JAK2 I682 and R683 map to the junction between the
N and C lobes of the pseudokinase domain (Fig. S3A). All 4
pseudokinase domain mutations identified affect these residues
and are predicted to influence the structure and dynamics of the
loops that pack together at the interlobe interface, and this may
result in a loss of the inhibitory activity of the pseudokinase
domain. Accordingly, the R683G and R683S mutations result in
the activation of the tyrosine kinase activity of JAK2 (10, 11).
R867Q and D873N map to the ?2-?3 loop of the kinase domain
and are predicted to alter surface electrostatic properties of this
region, adjacent to the ATP-binding site (22), and is thought to
impart rigidity to this hinge that may be important for catalytic
activity. These data suggest that the kinase mutations may lead
to enhanced kinase activity.
In Vitro Analysis of JAK Mutations. To examine the functional
consequences of the JAK variants, we transduced murine pro-B
Ba/F3 cells expressing the erythropoietin receptor (Ba/F3-EpoR
cells) with retroviral constructs expressing wild-type or mutant
murine Jak1 or Jak2 alleles. Each Jak mutation examined
2 A and B) and resulted in constitutive Jak-Stat activation, as
assessed by western blotting (Fig. 2E), and by phosphoflow
cytometry analysis of Jak2 and Stat5 phosphorylation after
serum and cytokine starvation and subsequent erythropoietin or
pervanadate stimulation (Fig. 3A and C). Interestingly, expres-
sion of the Jak2 pseudokinase domain mutants resulted in
higher growth rates and Jak-Stat phosphorylation than that
observed for the Jak2 kinase domain mutants (Figs. 2 A and E
and 3 A and C).
This transformation was abrogated by the pan-Jak-specific
inhibitor Jak inhibitor I (Fig. 2 C, D, and F). The Jak2 inhibitor
XL019 abrogated ligand-induced Jak-Stat activation induced by
all tested Jak2 mutants (Fig. 3B). Treatment of the cells with the
tyrosine phosphatase inhibitor pervanadate led to greater levels
of Jak2 and Stat5 phosphorylation (Fig. 3C), which was more
completely inhibited for mutations involving the pseudokinase
domain than the kinase domain (Fig. 3D). The basis of this
variable inhibition is unknown but raises the possibility of
differences in the mechanism of transformation induced by each
Similarity of the Gene Expression Profiles of JAK-Mutated and BCR-
ABL1-Positive ALL. The similarity in gene expression signatures
between IKZF1-deleted BCR-ABL1-positive and BCR-ABL1-
negative ALL suggested the possibility of activated tyrosine
kinase signaling in the BCR-ABL1-negative cases (4). As ex-
pected, the JAK-mutated cases exhibited a BCR-ABL1-like gene
expression signature (Fig. 4 A and B). Notably, additional
IKZF1-mutated cases that lacked JAK mutations also showed
enrichment of the BCR-ABL1-like signature (Fig. 4B), suggest-
ing that these cases may harbor additional tyrosine kinase or
JAK Mutations and IKZF1 Alteration Are Associated with Poor Out-
come in Pediatric ALL. We observed highly significant associations
between IKZF1 and JAK lesions and outcome. The 4-year
cumulative incidence of events (relapse, death, or second ma-
lignancy) was 78.2% for patients with both a JAK mutation and
IKZF1 alteration, compared with 54.4% for IKZF1 alteration
only, 33.3% for JAK mutation only, and 24.3% for neither lesion
(P ? 0.0002; Fig. 4C). This was primarily attributable to differ-
ences in the risk of relapse. The 4-year cumulative incidence of
relapse was 76.6% for patients with both a JAK mutation and
IKZF1 alteration, compared with 53.6% for IKZF1 alteration
only, 33.3% for JAK mutation only, and 23.2% for neither lesion
(P ? 0.0004; Fig. 4D). In multivariable analyses incorporating
clinical and laboratory variables, there was a trend toward an
association between JAK mutations and increased risk of events
or relapse (Table S4). However, no independent association was
observed after incorporation of IKZF1 status in the model
missense (?) and insertion/deletion (Œ) mutations. FERM, band 4.1 ezrin,
radixin, and moesin domain; SH2, src-homology domain; JH2, pseudokinase
domain; and JH1, kinase domain.
Primary structure of JAK1, JAK2, and JAK3 showing the location of
Mullighan et al.PNAS ?
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of JAK mutations and IKZF1 alterations. Moreover, additional
IKZF1-mutated, JAK wild-type cases also have a ‘‘BCR-ABL1-
like’’ signature and poor outcome, suggesting additional uniden-
tified kinase-activating lesions in these cases.
These results demonstrate that JAK kinase mutations are not
limited to patients with DS-ALL, but also occur in about 10% of
high-risk pediatric B-progenitor ALL patients. Notably, the
independence. (C) Ba/F3-EpoR cells transduced with wild-type or mutant Jak2 were cultured without cytokine in the presence of increasing concentrations of
S646F was inhibited by Jak inhibitor I. (E) Western blots showing activation of JAK-STAT signaling in Ba/F3-EpoR cells transduced with each mutant Jak allele.
Cells were cultured without erythropoietin for 15 h and then harvested for blotting before and after 15 min of erythropoietin at 5 units/mL. Each mutation
resulted in constitutive Jak2 and Stat5 phosphorylation that was augmented by pulsed erythropoietin (shown for Jak2 617F and 683G). The Jak2 kinase domain
mutations showed less constitutive Jak-Stat activation than the pseudokinase domain mutations. Epo, erythropoietin; WT, wild type. (F) Western blots
demonstrating abrogation of Jak-Stat activation by Jak inhibitor I. Ba/F3-EpoR cells transduced with each Jak allele were grown in the absence of cytokine, then
harvested after 5 h of exposure to 5 mM Jak inhibitor I or vehicle (DMSO).
Functional effects of JAK mutations. (A) Ba/F3-EpoR cells were transduced with retroviruses expressing wild-type or mutant Jak2 alleles and cultured
www.pnas.org?cgi?doi?10.1073?pnas.0811761106 Mullighan et al.
P9906 cohort studied here is not an unselected series of child-
hood ALL cases, but comprises patients with high white blood
cell counts and/or older age that were predicted to have a poor
outcome. Patients with high hyperdiploidy, hypodiploidy, ETV6-
RUNX1, or BCR-ABL1 were not included; however, the cohort
did include TCF3-PBX1 (n ? 22) and MLL-rearranged (n ? 18)
B-progenitor cases, none of whom had JAK mutations. These
differences in cohort composition provide a potential explana-
tion as to why JAK mutations have not been detected more
frequently in non-DS-ALL in other studies (10, 11). Future
studies including larger numbers of patients with recurring
cytogenetic alterations will be of interest to determine whether
JAK mutations occur predominantly among ALL patients lack-
ing known translocations and aneuploidy.
JAK mutations were associated with concomitant IKZF1 and
CDKN2A/B alterations, suggesting that genetic lesions targeting
multiple cellular pathways, including lymphoid development
(IKZF1), tumor suppression (CDKN2A/B), and activation of
tyrosine kinases (BCR-ABL1, JAK, or other kinase mutations)
cooperate to induce aggressive lymphoid leukemia in both
DS-ALL and non-DS-ALL that is resistant to conventional ALL
therapy. The majority of the identified JAK mutations occur in
the pseudokinase domain of JAK2 in a region (R683) distinct
from the predominant mutation (V617F) seen in polycythemia
vera and related myeloproliferative diseases (9). It has been
hypothesized that the nature of the JAK mutation plays a direct
role in establishing the disease phenotype (9, 23, 24), and
mutations at R683 have been identified almost exclusively in
DS-ALL-related ALL (10, 11). Experiments testing the in
vivo-transforming activity of the JAK mutations and the coop-
erative effect of concomitant genetic lesions, such as alteration
of IKZF1, should provide valuable insights into how these lesions
contribute to leukemogenesis and treatment resistance. Notably,
both DS-ALL cases with JAK mutations in this study had
concomitant alterations of IKZF1 and CDKN2A/B, suggesting
that the cooccurrence of these lesions is important in the
pathogenesis of DS and non-DS high-risk ALL. The identifica-
tion of JAK mutations in a subset of the IKZF1-mutated,
poor-outcome group raises the possibility that inhibition of JAK
activity will be a logical therapeutic approach in these patients.
Indeed, our data demonstrate impressive inhibition of the Jak-
Stat activation induced by Jak pseudokinase domain mutations
by the JAK2 inhibitor XL019, a drug currently in early-phase
trials for myeloproliferative disorders. Finally, the absence of
JAK mutations in additional cases with a BCR-ABL1-like ex-
pression signature suggests that efforts to identify the causes of
activated kinase signaling in these cases should identify addi-
tional therapeutic targets in high-risk pediatric ALL.
Materials and Methods
Patients and Treatment. Patients were enrolled in the Children’s Oncology
Group P9906 trial and treated with an augmented reinduction/reconsolida-
cells transduced with Jak2 retroviral constructs. Transduced cells were serum-
starved and cytokine-starved and then stimulated either with erythropoietin
inhibition (A and C) or after administration of the Jak2 inhibitor XL019 (B and
D). (A) Activation of Jak-Stat phosphorylation with erythropoietin stimula-
tion. Notably, Jak2 phosphorylation was evident for Jak2 pseudokinase mu-
tant alleles but not the kinase domain mutants. (B) Signaling was abrogated
in control and mutants treated with XL019 with subsequent erythropoietin
stimulation. (C) Marked Jak2 and Stat5 phosphorylation was observed for
each mutant after pervanadate stimulation. (D) Jak2 and Stat5 signaling was
preferentially abrogated in mutants treated with XL019 with subsequent
Phosphoflow cytometry analysis of Jak-Stat activation in Ba/F3-EpoR
ALL. (A) Gene set enrichment analysis demonstrates significant enrichment of
the BCR-ABL1 gene expression signature in JAK-mutated ALL. (B) Heatmap of
the enriched BCR-ABL1 up-regulated gene set in the P9906 cohort, showing
overexpression of BCR-ABL1 up-regulated genes in JAK-mutated ALL. Nota-
bly, several cases lacking JAK mutations also have a BCR-ABL1 signature,
suggesting the presence of additional kinase mutations in these cases. (C and
D) JAK mutation and IKZF1 alteration are associated with a high incidence of
events (C) and relapse (D).
Gene expression profile and outcome of JAK-mutated B-progenitor
Mullighan et al. PNAS ?
June 9, 2009 ?
vol. 106 ?
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tion strategy (5). All patients were high-risk based on the presence of central Download full-text
as cases of primary induction failure were excluded. The cohort is described
further in the SI Methods.
Genomic Resequencing and Structural Modeling of JAK2 Mutations. Resequenc-
ing of the coding exons of JAK1, JAK2, JAK3, and TYK2 was performed by
Agencourt Biosciences. Sequencing, sequence analysis, structural modeling,
and homology alignment of JAK mutations are described in the SI Methods.
Functional Assays of JAK Mutants. The JAK1 S646F and JAK2 V617F, I682F,
R683G, R683S, D873N, and P933R mutations were introduced into the bicis-
tronic MSCV-IRES-GFP retroviral vector encoding either murine Jak1 or Jak2
containing the C-terminal HA tag (26) by site-directed mutagenesis
(QuikChange XL II; Stratagene). Retroviral supernatants were produced by
using ecotropic Phoenix packaging cells (G.P. Nolan; www.stanford.edu/
group/nolan/). Murine pro-B Ba/F3 cells were transduced with MSCV-EpoR-
or mutant Jak retroviral supernatants. Transduced cells were purified by flow
sorting for GFP and were maintained in RPMI-1640 with 10% FCS (HyClone)
penicillin-streptomycin, L-glutamine, and 5 units/mL erythropoietin. To assess
growth factor independence, cells were washed 3 times and were plated at
500,000 cells per milliliter in media without cytokine, with or without JAK
counter (Beckman Coulter).
For Western blotting, Jak-transduced Ba/F3-EpoR cells were cultured for
15 h without erythropoietin, followed by 15 min of treatment with erythro-
poietin at 5 units/mL or vehicle (DMSO). Whole-cell lysates were blotted and
probed with anti-Jak2, anti-phospho-Jak2 (Tyr 1007–1008), anti-Stat5, and
anti-phospho-Stat5 (Cell Signaling Technology), and with anti-PCNA (Santa
Cytokine stimulation and intracellular phosphoprotein analysis using flow
cytometry was performed as described previously (27). Ba/F3-EpoR cells were
serum- and cytokine-starved for 30 min, then incubated with the JAK2 inhib-
itor XL019 (Exelixis) at a concentration of 5 ?M for 30 min. Control and
XL019-treated cells were subsequently stimulated with 5 ng/mL murine IL-3, 2
fixed, permeabilized, rehydrated overnight, and then stained with anti-
phospho-Stat5-Alexa 647 (Tyr-694; BD Biosciences), anti-phospho-Jak2 (Tyr
cytometer (BD Biosciences), and data were collected and analyzed by using
DIVA (BD Biosciences) and FlowJo (Tree Star).
Gene Set Enrichment Analysis (GSEA). GSEA (28) was performed as described
previously (2, 4) by using the collection of publicly available gene sets (www.
broad.mit.edu/gsea/msigdb/) and gene sets derived from the top up- and
down-regulated genes of BCR-ABL1 de novo pediatric ALL (29, 30).
Statistical Analysis. Associations between clinical, laboratory, and genetic
variables and outcome (event-free survival and relapse) were performed as
described previously (4). Cumulative incidence of relapse according to IKZF1
and JAK status was analyzed by using Gray’s test (31). Associations with
and the Mantel–Haenszel test (32). Multivariable analyses of event-free sur-
vival were performed by using the EFS-PHREG procedure in SAS version 9.1.3
Fine and Gray method (33) in S-Plus version 7.0.6 (Insightful).
ACKNOWLEDGMENTS. We thank E. Parganas and J. Ihle (St. Jude Children’s
Research Hospital, Memphis, TN) for murine Jak and EpoR-puro retroviral
constructs, and D. Clary (Exelixis) for providing XL019. The correlative biology
studies described in this manuscript were funded by grants, funds from the
National Institutes of Health (NIH), and philanthropic funds of the Children’s
Oncology Group, and not by a commercial entity. This work was supported by
funds provided as a supplement to the Children’s Oncology Group Chair’s
Award CA098543 (to S.P.H.); National Cancer Institute (NCI) Strategic Partner-
ing to Evaluate Cancer Signatures (SPECS) Program Award CA114762 (to
W.L.C., I.-M.C., R.C.H., and C.L.W.); NIH Cancer Center Core Grant 21765 (to
J.R.D. and C.G.M.); NCI Grant U10 CA98543 supporting the TARGET initiative,
the Children’s Oncology Group, and U10 CA98413 supporting the Statistical
Center (to G.H.R); Leukemia and Lymphoma Society Specialized Center of
Research Grant 7388-06 (to C.L.W.); NCI Grant P30 CA118100 (to C.L.W)
supporting the University of New Mexico Cancer Center Shared Resources;
CureSearch; St. Baldrick’s Foundation (M.L.L.); a National Health and Medical
Research Council (Australia) CJ Martin Traveling Fellowship (to C.G.M.); and
the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Chil-
dren’s Research Hospital. B.A.S. is an investigator of the Howard Hughes
Medical Institute. S.P.H. is the Ergen Family Chair in Pediatric Cancer. The
National Institutes of Health, Contract N01-C0-12400.
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