High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2992-2996 ◽  
Author(s):  
Jeffrey W. Taub ◽  
Mark A. Konrad ◽  
Yubin Ge ◽  
John M. Naber ◽  
Jackie S. Scott ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Newborn Screening ◽  
Lymphoblastic Leukemia ◽  
In Utero ◽  
Leukemia Cells ◽  
Patient Specific ◽  
Childhood All ◽  
Blood Samples ◽  
Leukemic Clone ◽  
Study Support

Abstract The detection of leukemia cells on newborn genetic screening cards (“Guthrie cards”) of a small group of patients and several sets of identical twins developing acute lymphoblastic leukemia (ALL) with identical phenotypic and chromosomal markers has provided evidence that childhood ALL cases may arise in utero. We conducted a retrospective study of a randomly selected group of childhood B-precursor ALL patients to determine the frequency of the presence of “leukemic” clones prenatally in ALL cases by testing newborn screening cards. The 17 ALL patients analyzed had a median age of 46 months (range, 18 months to 13 years) and had median presenting white blood cell (WBC) counts of 10 950/μL (range, 2900-70 300/μL) at diagnosis. A clonal rearrangement of the immunoglobulin heavy chain (IgH) gene was identified in diagnostic lymphoblasts and sequenced and patient-specific primers were used to amplify DNA from blood samples on the patient's newborn screening cards. Twelve of the 17 (71%) analyzed newborn cards had detectable IgH rearrangements amplified by seminested polymerase chain reaction. DNA sequencing confirmed that the IgH rearrangements detected matched the IgH sequences identified from diagnostic leukemia cells, indicating the presence of a “leukemic” clone at birth. There were no differences in age or presenting WBC counts between the cases with or without positive newborn screening cards. All 6 patients with hyperdiploid ALL had detectable “leukemic” clones on their cards. The results of our study support the notion that a high proportion of childhood B-precursor ALL cases arise in utero, although postnatal events are also important factors in leukemogenesis.

scholarly journals Evidence for clonal development of childhood acute lymphoblastic leukemia

Blood ◽  
1985 ◽  
Vol 66 (4) ◽  
pp. 902-907
Author(s):  
LW Dow ◽  
P Martin ◽  
J Moohr ◽  
M Greenberg ◽  
LG Macdougall ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Progenitor Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Childhood All ◽  
Hla Dr ◽  
Blast Cells ◽  
Leukemic Clone ◽  
Clonal Development ◽  
Glucose 6 Phosphate Dehydrogenase

To determine whether acute lymphoblastic leukemia (ALL) is a clonal disease and to define the pattern of differentiation shown by the involved progenitor cells, we studied the glucose-6-phosphate dehydrogenase (G6PD) types in the cells of 19 girls heterozygous for this X chromosome-linked enzyme. Lymphoblast immunophenotypes were those of HLA-DR+, CALLA+ ALL (six patients); HLA-DR+, CALLA- ALL (four patients); pre-B cell ALL (two patients); T cell ALL (four patients); and undefined ALL (three patients). Malignant blast cells at diagnosis from ten patients displayed a single G6PD type, indicative of clonal disease. In contrast, both A and B G6PD in ratios similar to those found in skin were observed in morphologically normal blood cells from the same patients. The leukemic cells of three patients were examined at both diagnosis and relapse; in each instance the same G6PD type was found, consistent with regrowth of the original leukemic clone at relapse. Results of studies of cells from nine additional patients tested only at relapse were similar. Our results indicate that childhood ALL is a clonally derived disease involving progenitor cells with differentiation expression detected only in the lymphoid lineage.

Folate Pathway Gene Expression Differs in Genetic Subtypes of Acute Lymphoblastic Leukemia and Influences Methotrexate Pharmacodynamics.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 452-452
Author(s):  
Leo Kager ◽  
Meyling H. Cheok ◽  
Wenjian Yang ◽  
Gianluigi Zaza ◽  
Ching-Hon Pui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Cancer Resistance ◽  
Childhood All ◽  
Pathway Gene ◽  
Folate Pathway ◽  
B Lineage ◽  
Lower Expression

Abstract Methotrexate (MTX) is an essential treatment component for acute lymphoblastic leukemia (ALL). The ability of leukemia cells to accumulate MTX in its polyglutamylated form (MTXPG) is recognized as an important determinant of its antileukemic effect. We measured in vivo MTXPG accumulation in leukemia cells from 101 children with ALL, and established that blasts of B-lineage ALL with either the TEL-AML1 (n=24 patients, median 911, range 338 to 5906 pmol/109 blasts) or E2A-PBX1 gene fusion (n=5, median 553, range 364 to 800 pmol/109 blasts) or T-lineage ALL (n=14, median 572, range 284 to 1468 pmol/109 blasts) accumulate significantly lower MTXPG, compared to those of other B-lineage ALL (BNHD, n=39, median 2210, range 186 to 9722 pmol/109 blasts) or hyperdiploid ALL (BHD, n=19, median 4375, range 377 to 9206 pmol/109 blasts) (E2A-PBX1 versus BHD, p=0.008; E2A-PBX1 vs. BNHD, p=0.010; TEL-AML1 vs. BHD, p<0.001; TEL-AML1 vs. BNHD, p=0.004; T-ALL vs. BHD and BNHD, p<0.001; p-values are from pair-wise comparisons using Wilcoxon rank sum test, adjusted for multiple testing using Holm’s method). To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays (Affymetrix® HG-U133A) to analyze expression of 32 folate pathway genes (53 probe sets) in diagnostic bone marrow blasts from 197 children with ALL. This revealed ALL subtype-specific patterns of folate metabolism gene expression and identified differences in gene expression that discriminated the MTXPG accumulation phenotype in ALL cells. We found significantly lower expression of the reduced folate carrier (SLC19A1, MTX uptake transporter) in E2A-PBX1 ALL; significantly higher expression of breast cancer resistance protein (ABCG2, MTX efflux transporter) in TEL-AML1 ALL; and lower expression of FPGS (catalyzes formation of MTXPG) in T-ALL; consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome this potential cause of treatment failure in childhood ALL.

scholarly journals Evolution of Tumor Clones in Adult Acute Lymphoblastic Leukemia

Acta Naturae ◽  
2016 ◽  
Vol 8 (4) ◽  
pp. 100-109 ◽  
Author(s):  
S. Yu. Smirnova ◽  
Yu. V. Sidorova ◽  
N. V. Ryzhikova ◽  
K. A. Sychevskaya ◽  
E. N. Parovichnikova ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Disease Onset ◽  
Disease Recurrence ◽  
Detection Sensitivity ◽  
Patient Specific ◽  
Gene Rearrangements ◽  
Childhood All

Clonal instability of a tumor cell population in acute lymphoblastic leukemia (ALL) may complicate the monitoring of a minimal residual disease (MRD) by means of patient-specific targets identified at the disease onset. Most of the data concerning the possible instability of rearranged clonal TCR and IG genes during disease recurrence were obtained for ALL in children. The appropriate features of adult ALL, which are known to differ from those of childhood ALL in certain biological characteristics and prognosis, remain insufficiently studied. The aim of this study was to assess the stability of IG and TCR gene rearrangements in adult ALL. Rearrangements were identified according to the BIOMED-2 protocol (PCR followed by fragment analysis). Mismatch in clonal rearrangements at onset and relapse was identified in 83% of patients, indicating clonal instability during treatment. Clonal evolution and diversity of IG and TCR gene rearrangements may be one of the tumor progression mechanisms. New rearrangements may emerge due to residual VDJ-recombinase activity in tumor cells. Also, many clonal IG and TCR gene rearrangements may be present at different levels at a diagnosis, but less abundant clones may be invisible due to limited detection sensitivity. Later, major clones may disappear in the course of chemotherapy, while others may proliferate. Investigation of clonal evolution and heterogeneity in ALL and their impact on the treatment efficacy will contribute to the identification of new prognostic factors and the development of therapeutic approaches.

Presence of clone-specific antigen receptor gene rearrangements at birth indicates an in utero origin of diverse types of early childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2722-2724 ◽  
Author(s):  
Karin Fasching ◽  
Simon Panzer ◽  
Oskar A. Haas ◽  
Rolf Marschalek ◽  
Helmut Gadner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Specific Antigen ◽  
Antigen Receptor ◽  
In Utero ◽  
Gene Rearrangements ◽  
Fetal Life ◽  
Childhood All

Abstract There is strong evidence that infant leukemias with a t(4;11) translocation originate in utero. To test whether other subtypes of childhood leukemias are also initiated during fetal life, we used clone-specific genetic markers for the analysis of neonatal blood spots from 5 children aged 6 months to 4 years 8 months at diagnosis of pro-B, common acute lymphoblastic leukemia (ALL), and T-ALL. In all children, the clonotypic antigen receptor gene rearrangements were already present at birth. The estimated amount of clonotypic cells was in the range of 10 to 100 cells per blood spot. In 2 infants with a t(4;11) positive ALL, we detected similar amounts of the fusion gene sequences compared with the clonal antigen receptor gene rearrangements, suggesting the presence of both markers in the same cells. Our data indicate that the first leukemogenic event of diverse types of childhood ALL may already occur in utero.

Presence of clone-specific antigen receptor gene rearrangements at birth indicates an in utero origin of diverse types of early childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2722-2724
Author(s):  
Karin Fasching ◽  
Simon Panzer ◽  
Oskar A. Haas ◽  
Rolf Marschalek ◽  
Helmut Gadner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Specific Antigen ◽  
Antigen Receptor ◽  
In Utero ◽  
Gene Rearrangements ◽  
Fetal Life ◽  
Childhood All

There is strong evidence that infant leukemias with a t(4;11) translocation originate in utero. To test whether other subtypes of childhood leukemias are also initiated during fetal life, we used clone-specific genetic markers for the analysis of neonatal blood spots from 5 children aged 6 months to 4 years 8 months at diagnosis of pro-B, common acute lymphoblastic leukemia (ALL), and T-ALL. In all children, the clonotypic antigen receptor gene rearrangements were already present at birth. The estimated amount of clonotypic cells was in the range of 10 to 100 cells per blood spot. In 2 infants with a t(4;11) positive ALL, we detected similar amounts of the fusion gene sequences compared with the clonal antigen receptor gene rearrangements, suggesting the presence of both markers in the same cells. Our data indicate that the first leukemogenic event of diverse types of childhood ALL may already occur in utero.

scholarly journals Evidence for clonal development of childhood acute lymphoblastic leukemia

Blood ◽  
1985 ◽  
Vol 66 (4) ◽  
pp. 902-907 ◽  
Author(s):  
LW Dow ◽  
P Martin ◽  
J Moohr ◽  
M Greenberg ◽  
LG Macdougall ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Progenitor Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Childhood All ◽  
Hla Dr ◽  
Blast Cells ◽  
Leukemic Clone ◽  
Clonal Development ◽  
Glucose 6 Phosphate Dehydrogenase

Abstract To determine whether acute lymphoblastic leukemia (ALL) is a clonal disease and to define the pattern of differentiation shown by the involved progenitor cells, we studied the glucose-6-phosphate dehydrogenase (G6PD) types in the cells of 19 girls heterozygous for this X chromosome-linked enzyme. Lymphoblast immunophenotypes were those of HLA-DR+, CALLA+ ALL (six patients); HLA-DR+, CALLA- ALL (four patients); pre-B cell ALL (two patients); T cell ALL (four patients); and undefined ALL (three patients). Malignant blast cells at diagnosis from ten patients displayed a single G6PD type, indicative of clonal disease. In contrast, both A and B G6PD in ratios similar to those found in skin were observed in morphologically normal blood cells from the same patients. The leukemic cells of three patients were examined at both diagnosis and relapse; in each instance the same G6PD type was found, consistent with regrowth of the original leukemic clone at relapse. Results of studies of cells from nine additional patients tested only at relapse were similar. Our results indicate that childhood ALL is a clonally derived disease involving progenitor cells with differentiation expression detected only in the lymphoid lineage.

scholarly journals Maternal Haplotypes in DHFR Promoter and MTHFR Gene in Tuning Childhood Acute Lymphoblastic Leukemia Onset-Latency: Genetic/Epigenetic Mother/Child Dyad Study (GEMCDS)

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 634 ◽  
Author(s):  
Veronica Tisato ◽  
Paola Muggeo ◽  
Tracy Lupiano ◽  
Giovanna Longo ◽  
Maria Luisa Serino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Early Onset ◽  
Lymphoblastic Leukemia ◽  
In Utero ◽  
Mthfr Gene ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Strong Linkage Disequilibrium ◽  
Onset Age ◽  
Childhood All ◽  
Mthfr A1298c

Childhood acute lymphoblastic leukemia (ALL) peaks around age 2–4, and in utero genetic epigenetic mother-fetus crosstalk might tune ALL onset during childhood life. Folate genes variably interact with vitamin status on ALL risk and prognosis. We investigated DHFR and MTHFR gene variants in 235 ALL children and their mothers to disclose their role in determining ALL onset age and survival. Pyrosequence of DHFR 19bp ins/del (rs70991108; W/D), MTHFR C677T (rs1801133; C>T), and MTHFR A1298C (rs1801131; A>C) was assessed in children and in 72% of mothers for dyad-analysis comparison. DHFR DD-children had delayed ALL onset compared to WW-children (7.5 ± 4.8 vs. 5.2 ± 3.7 years; P = 0.002) as well as MTHFR 1298 CC-children compared to AA-children (8.03 ± 4.8 vs. 5.78 ± 4.1 years; P = 0.006), and according to the strong linkage disequilibrium between MTHFR 677 T-allele and 1298C-allele, MTHFR TT-children showed early mean age of onset though not significant. Offspring of MTHFR 677 TT-mothers had earlier ALL onset compared to offspring of 677 CC-mothers (5.4 ± 3.3 vs. 7 ± 5.3 years; P = 0.017). DHFR/MTHFR 677 polymorphism combination influenced onset age by comparing DD/CC vs. WW/TT children (8.1 ± 5.7 vs. 4.7 ± 2.1 years; P = 0.017). Moreover, mother-child genotype combination gave 5.5-years delayed onset age in favor of DD-offspring of 677 CC-mothers vs. WW-offspring of 677 TT-mothers, and it was further confirmed including any D-carrier children and any 677 T-carrier mothers (P = 0.00052). Correction for multiple comparisons maintained statistical significance for DHFR ins/del and MTHFR A1298C polymorphisms. Unexpectedly, among the very-early onset group (<2.89 years; 25th), DD-genotype inversely clustered in children and mothers (4.8% vs. 23.8% respectively), and accordingly ALL offspring of homozygous DD-mothers had increased risk to have early-onset (adjusted OR (odds ratio) = 3.08; 1.1–8.6; P = 0.03). The opposite effect DHFR promoter variant has in tuning ALL onset-time depending on who is the carrier (i.e., mother or child) might suggest a parent-origin-effect of the D-allele or a two-faced epigenetic role driven by unbalanced folate isoform availability during the in-utero leukemogenesis responsible for the wide postnatal childhood ALL latency.

BACH2 Mediates Early B Cell Differentiation and Oncogene-Induced Senescence in Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 562-562
Author(s):  
Srividya Swaminathan ◽  
Chuanxin Huang ◽  
Bjorn Titz ◽  
Maike Buchner ◽  
Huimin Geng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Mrna Levels ◽  
B Cell Differentiation ◽  
Childhood All ◽  
Btb Domain

Abstract Abstract 562FN2 Background: The BACH2 (BTB and CNC homology, basic leucine zipper transcription factor 2) transcription factor is required for class-switch recombination and somatic hypermutation of immunoglobulin genes during affinity maturation of mature germinal center B cells. Interestingly, we and others found that BACH2 is strongly upregulated in BCR-ABL1-transformed acute lymphoblastic leukemia (Ph+ ALL) cells upon treatment with tyrosine kinase inhibitors (TKI). Results: Bach2 mRNA levels are significantly lower in Ph+ ALL (n=72) compared to normal human bone marrow pre-B cells (n=10). We next studied 49 samples pairs from patients with childhood ALL at diagnosis and relapse. In 44 of these sample pairs, the relapse sample showed drastically reduced mRNA levels of Bach2 (p=0.019), suggesting that loss of BACH2 expression is associated with relapse of childhood ALL. Consistent with these findings, an independent study (Children's Oncology Group; NCT00005603) demonstrated that BACH2 mRNA levels in childhood ALL samples at diagnosis negatively correlated with early minimal residual disease (MRD) findings on day 29 (n=207; p<0.0001). Compared to normal pre-B cells (n=5), CpG islands in the BACH2 promoter were hypermethylated in Ph+ ALL cells (n=70). A detailed sequence analysis of the BACH2 coding region in 10 primary cases of Ph+ ALL revealed 7 unique point mutations including 5 amino acid changes in the BACH2 BTB domain. These findings suggest that BACH2 is affected by somatic mutations in a fraction of cases of Ph+ ALL. To study the role of Bach2 in pre-B ALL in a genetic experiment, we transformed pre-B cells from Bach2−/− mice with BCR-ABL1. An Affymetrix GeneChip analysis revealed that many of the genes that are differentially expressed between Bach2+/+ and Bach2−/− ALL cells are shared with a common gene expression signature reflecting TKI-treatment and inducible deletion of Myc or Stat5a/Stat5b. Interestingly, Bach2−/− normal pre-B cells lack the ability to upregulate expression of Rag1 and Rag2. The two Rag enzymes are required for Vk-Jk gene recombination and as a consequence, Bach2−/− pre-B cells fail to differentiate into k light chain expressing B cells. Besides this unexpected role in early B cell differentiation, quantitative RT-PCR and Western blot confirmed that Bach2 is also required for expression of the tumor suppressors Cdkn2a (Arf), p53 and Btg2. Consistent with extremely low protein levels of Arf and p53 in Bach2−/− leukemia cells, Bach2−/− ALL cells are more resistant to Imatinib-treatment, more actively proliferating (increased S-phase; p=0.02) and exhibit a ∼90-fold increased ability to form colonies in methyl cellulose (p=0.001). While BCR-ABL1-transformed pre-B ALL cells already express Myc at high levels, forced overexpression of Myc through a retroviral vector results in oncogene-induced senescence (OIS; senescence-associated b-galactosidase+) and subsequent apoptosis (Annexin V+). Whereas Bach2+/+ leukemia cells are non-permissive to forced Myc expression and die within four days following OIS, Bach2−/− ALL cells tolerate forced expression of Myc and evade OIS and subsequent cell death. Similarly, overexpression of Myc alone fails to transform Bach2+/+ pre-B cells. By contrast, retroviral overexpression of Myc results in rapid transformation and growth factor-independence of Bach2−/− pre-B cells. Bach2−/− Myc-high pre-B cells cause fatal leukemia in 100% of recipient mice within 22 days, whereas all mice that received Bach2+/+ Myc-high pre-B cells survived without signs of disease until day 67, when all mice were sacrificed and analyzed for MRD by flow cytometry and PCR. No evidence of MRD was detected in most mice injected with Bach2+/+ Myc-high pre-B cells. Three mice had positive MRD PCR findings, however, at 4 log orders below findings in mice injected with Bach2−/− Myc-high pre-B cells. Conclusions: These findings collectively identify Bach2 as a barrier mechanism against malignant transformation of pre-B cells. Bach2 is required for induction of Arf and p53 expression in the context of OIS. BACH2 is often hypermethylated at its promoter or somatically mutated in regions encoding its BTB domain. Consistent with these findings, lack of Bach2 mRNA expression is predictive of positive MRD at day 29 and associated with relapse of childhood ALL. Disclosures: No relevant conflicts of interest to declare.

Protracted and Variable Latency of Acute Lymphoblastic Leukemia AfterTEL-AML1 Gene Fusion In Utero

Blood ◽  
1999 ◽  
Vol 94 (3) ◽  
pp. 1057-1062 ◽  
Author(s):  
Joseph L. Wiemels ◽  
Anthony M. Ford ◽  
Elisabeth R. Van Wering ◽  
Aleida Postma ◽  
Mel Greaves
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
In Utero ◽  
Leukemic Cells ◽  
Long Distance ◽  
History Of Childhood ◽  
History Of ◽  
Leukemic Clone ◽  
Pcr Method

We report a pair of identical twins with concordant acute lymphoblastic leukemia (ALL). Unusually, their diagnoses were spaced 9 years apart at ages 5 and 14. Leukemic cells in both twins had aTEL-AML1 rearrangement, which was characterized at the DNA level by an adaptation of a long distance polymerase chain reaction (PCR) method. The genomic fusion sequence was identical in the two leukemias, indicative of a single cell origin in one fetus, in utero. At the time twin 1 was diagnosed (aged 5 years), the bone marrow of twin 2 was hematologically normal. However, retrospective scrutiny of the DNA from an archived slide with clonotypic TEL-AML1 primers showed that the presumptive preleukemic clone was present and disseminated 9 years before a clinical diagnosis. These data provide novel insight into the natural history of childhood leukemia and suggest that consequent to a prenatal initiation of a leukemic clone, most probably by TEL-AML fusion itself, the latency of ALL can be both extremely variable and protracted. This, in turn, is likely to reflect the timing of critical secondary events.

The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4100-4108 ◽  
Author(s):  
Richard B. Lock ◽  
Natalia Liem ◽  
Monica L. Farnsworth ◽  
Christopher G. Milross ◽  
Chengyuan Xue ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Scid Mice ◽  
Patient Specific ◽  
Coding Region ◽  
Childhood All ◽  
Prognostic Features ◽  
Nonobese Diabetic

Acute lymphoblastic leukemia cells from 19 children, including 7 who remain in first complete remission (CR1), were engrafted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. High-level infiltration of bone marrow, spleen, and liver was observed, with variable infiltration of other organs. The immunophenotypes of xenografts were essentially unaltered compared with the original patient sample. In addition, sequencing of the entire p53 coding region revealed no mutations in 14 of 14 xenografts (10 from patients at diagnosis and 4 at relapse). Cells harvested from the spleens of engrafted mice readily transferred the leukemia to secondary and tertiary recipients. To correlate biologic characteristics of xenografts with clinical and prognostic features of the patients, the rates at which individual leukemia samples engrafted in NOD/SCID mice were analyzed. Differences in biologic correlates were encountered depending on stage of disease: a direct correlation was observed between the rate of engraftment and length of CR1 for samples harvested at relapse (r = 0.96; P = .002), but not diagnosis (r = 0.38; P = .40). In contrast, the in vivo responses of 6 xenografts to vincristine showed a direct correlation (r = 0.96; P = .002) between the length of CR1 and the rate at which the leukemia cell population recovered following vincristine treatment, regardless of whether the xenografts were derived from patients at diagnosis or relapse. This study supports previous findings that the NOD/SCID model of childhood ALL provides an accurate representation of the human disease and indicates that it may be of value to predict relapse and design alternative treatment strategies in a patient-specific manner.

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