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  • American Society of Hematology  (13)
  • 1
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    Online Resource
    Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1425-1425
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1425-1425
    Abstract: Introduction Clinical outcome of relapsed pediatric B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remains poor, although survival rate for children with BCP-ALL has greatly increased over time and is now reached 90%. To clarify the molecular pathogenesis of relapsed ALL may provide novel prognostic markers and therapeutic targets. Some genome-wide analyses for specific patients group with poor prognosis, such as early-relapsed patients and Ph- or BCR-ABL-like patients, were reported. They described important insights to understand genetic background of poor prognosis. However, the majority of relapsed cases did not have any poor prognostic marker, and the molecular mechanisms of relapse in these cases still remained unclear. Therefore we performed whole exome sequencing (WES) to describe clonal evolution in 21 relapsed pediatric BCP-ALL patients. Our cohort included various cases whose time to relapse from diagnosis were between 6 months to over 10 years. We also analyzed the clonality of leukemia cells using immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements. Patients and Methods Genomic DNA was isolated from 21 cases whose median time to relapse was 33 months. Somatic mutations including SNVs (single nucleotide variants), insertions / deletions and CNVs (copy number variants) were detected by WES using Agilent SureSelect and illumine HiSeq systems. To evaluate accurate VAF (valiant allele frequency), targeted deep sequencing was performed in candidate somatic mutations. The clonality analysis of leukemia cells was performed by standard PCR methods using Ig and TCR rearrangements. Results WES was performed in samples obtained at diagnosis, remission and relapse from 21 pediatric BCP-ALL patients. Tumor specific mutations had been identified by WES. Three of 21 were hypermutated with over 150 somatic mutations at relapse. Mutation of DNA mismatch repair gene, MSH3, was detected in 2 of them. Except for these hypermutated cases, the median number of somatic mutations detected at relapsed phase was 22 (range 8 to 53), which was higher than that at diagnosis (median 16, range 6 to 31). Sixteen recurrently mutated genes were identified in 21 cases by WES. Some known leukemia associated genes were detected, including KRAS and WHSC1 observed only at diagnosis and IKZF1 and CREBBP observed at relapse. Then we compared VAFs of these mutations between at diagnosis and relapse to solve the clonal architectures over time. Three patterns of clonal evolution were estimated from VAFs using targeted deep sequencing; (i) In 7 cases, all mutations described at diagnosis were shared at relapse, suggesting that relapse clone derived from predominant clone at diagnosis with additional mutations in these cases. (ii) In other 13 cases, most of mutations in predominant clone at diagnosis were not detected at relapse except for some shared mutations at diagnosis and relapse, indicating that relapsed clone occurred from founder clone existing as subclone at diagnosis. (iii) In one very late-relapsed case, there were no shared mutations at diagnosis and relapse. According to clonality analysis of Ig and TCR, none of rearrangements identified at diagnosis were conserved at relapse in this case. On the other hand, most rearrangement at diagnosis were conserved at relapse in other 20 cases except one patient who relapsed in 10 years after diagnosis. Relapse from predominant clone at diagnosis were observed in only one out of 8 late-relapsed cases ( 〉 36 months), whereas a half of the early-relapsed showed this clonal evolution pattern. The number of shared mutations between diagnosis and relapse was very limited in very late-relapsed cases over 10 years. Discussion Our study suggests that the clonal evolution pattern differs according to the time to relapse. In a half of early-relapsed cases, relapsed clone derived from major clone at diagnosis with additional mutations, and clonal selection of resistant clones occurred during treatment. Meanwhile, in late-relapsed cases, relapse was frequently associated with clonal evolution from minor subclone with some conserved mutations and same Ig/TCR rearrangements. The founder clone should be remained dormant for a long period until additional mutations lead to relapse. Towards a better understanding of clonal evolution in ALL, our study will shed light on the early prediction of relapse risk and new treatment strategies for relapsed ALL. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1425.1425
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 2
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    Landscape of Driver Mutations and Their Clinical Impacts in Pediatric Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 912-912
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 912-912
    Abstract: Introduction B-progenitor acute lymphoblastic leukemia (B-ALLs) accounts for 85% of pediatric ALL and categorized into several molecular subgroups according to their ploidy and recurrent translocations, such as ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL-rearrangements. In addition, recent genetic studies using high-throughput sequencing have disclosed landscapes of gene alterations in each subgroup, however, their clinical relevance have not fully been investigated in a large cohort of B-ALL patients who are uniformly treated and enrolled in an unbiased manner. Methods We enrolled a total of 515 pediatric B-ALL patients, who had been uniformly treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol between 2002 and 2008. These patients were categorized into three risk groups, including standard-, high-, and extremely high-risk. Infantile ALL as well as BCR-ABL1-positive and Down syndrome-associated cases were excluded. A total of 158 known or putative driver genes in pediatric ALL were analyzed for somatic mutations by targeted-capture sequencing. IgH rearrangements were captured using 662 baits tiling the entire IgH enhancer locus. Finally, an additional 1205 baits was also designed to enable sequencing-based genome-wide copy number detection. Results The median age at diagnosis and observation period were 5.2 (1-18.5) and 4.2 (1.8-9) years, respectively. Sixty-six of the 515 patients (13%) had relapsed diseases and 47 patients (9%) had been died. Real-time RT-PCR and conventional cytogenetic analyses revealed subgroup-defining genetic lesions in 368/515 (71%) patients: 117 (23%) cases with ETV6-RUNX1, 48 (9%) with TCF3-PBX1, 13 (3%) with MLL rearrangements, together with those with hyper- (169 [33%]), and hypo- (6 [1%] ) diploid. Remaining 162 patients (31%) had none of these abnormalities. The mean depth of the targeted sequencing was 569× across the entire cohort. In total, 823 driver mutations (median 1 per patient, range 0-7) and 954 focal deletions (median 2 per patient, range 0-13) were detected in 483 patients (92%). Among these, most frequently detected were mutations/deletions in CDKN2A (24%), ETV6 (21%), NRAS (18%), KRAS (18%), and PAX5 (15%). IgH-rearrangements were detected in 51 patients, including IGH-DUX4 (26 [5.0%]), IGH-EPOR (3 [0.6%] ) and IGH-CRLF2(2 [0.3%]). Genetic alterations were enriched in several functional pathways, of which most frequent was epigenetic regulation (53%), followed by B-cell development (47%), RAS signaling (46%) and cell cycle (40%). A number of novel recurrent genetic lesions were also identified, including those in DOT1L and PHF6. DOT1L encode an H3K79 methyltransferase and was inactivated by frameshift/nonsense mutations and/or deletions in 19 cases. Although frequently found in T-ALL, mutations of PHF6 had not previously been reported in B-ALL but were detected in 14 cases in the current cohort and strongly associated with TCF3-PBX1 translocation. Significant positive correlations were also demonstrated for an additional 10 combinations of common genetic lesions, suggesting functional links between these combinations. Thus, ERG deletions were highly associated with IGH-DUX4 rearrangement, while mutations in KRAS, NRAS, and CREBBP were significantly enriched in hyperdiploid cases. ETV6-RUNX1 fusion also showed positive correlations with alterations in ETV6, CDKN1B, ATF7IP, VPREB1, BTG1, and WHSC1. Furthermore, mutually exclusive relationship between ETV6-RUNX1 translocationsand FLT3mutations were also identified. Finally, we analyzed the prognostic impact of driver mutations. In multivariate analysis of the entire cohort, 4 genetic alterations were significantly associated with poor prognosis (HR [95%CI]): IKZF1 mutations/deletions (2.6 [1.5−4.8] ), EBF1 deletions (3.0 [1.4−6.5]), KDM6A mutations/deletions (2.8 [1.2−6.5] ), and TP53 mutations (2.7 [1.2−5.9]). Additional factors (q 〈 0.1) were identified in subgroup analyses, including alterations in ETV6 (5.4 [1.2−24]), CDKN1B (7.4 [1.6−33] ) and CDKN2A (4.2 [1.4−12]) in ETV6-RUNX1 ALL, KMT2D (5.9 [1.3−26] ) in TCF3-PBX1 ALLand TP53 (38 [4.1−364]) in IGH-DUX4ALL. Conclusions We revealed the landscape of genetic lesions in pediatric B-ALL including novel targets of recurrent mutations with clinical relevance of common genetic lesions. Our results should help in the better stratification of patients. Disclosures Ogawa: Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.912.912
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 3
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    Landscape of driver mutations and their clinical impacts in pediatric B-cell precursor acute lymphoblastic leukemia
    American Society of Hematology ; 2020
    In:  Blood Advances Vol. 4, No. 20 ( 2020-10-27), p. 5165-5173
    Details
    In: Blood Advances, American Society of Hematology, Vol. 4, No. 20 ( 2020-10-27), p. 5165-5173
    Abstract: Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n = 116) and/or array-based gene expression analysis (n = 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n = 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2019001307
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 4
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    The Prognostic Value of TP53 Mutations Depends on Clinical Backgrounds in Pediatric Patients with Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4077-4077
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4077-4077
    Abstract: Introduction TP53 mutations in relapsed cases with pediatric acute lymphoblastic leukemia have been implicated in poor clinical outcomes. However, the prevalence and clinical significance of TP53 mutations at diagnosis have not been fully investigated. Such knowledge is essential for the care of patients, because treatment intensity is tailored to predictive prognosis, where increased attention has been directed toward de-escalation of treatment for the problem of long term effects and second malignancies in childhood cancer survivors. Methods Mutation status of TP53 was detected by targeted-capture sequencing of TP53 coding regions in 1,003 children with B-precursor ALL who had been treated in either of the two prospective clinical trials, JACLS (Japan Association of Childhood Leukemia Study) ALL-02 and TCCSG (Tokyo Children's Cancer Study Group) L04-16. Detection of common fusion genes, including BCR-ABL, ETV6-RUNX1, MLL-AF4, MLL-ENL, MLL-AF9, and TCF3-PBX1, were performed using qPCR assays. We designed SNP baits to analyze copy number status of chromosome 17, and also captured 662 probes tiling the entire IgH enhancer locus to identify IGH-DUX4 rearrangement. Result In total, 36 different non-silent coding TP53 mutations were identified in 30 (3%) patients, including 22 missense, 7 frameshift indel, 5 in-frame indel, and 2 nonsense mutations. All missense mutations were found in the core DNA-binding domain (n=21), except for one mutation, which affected the tetramerization motif. Variant allele frequencies (VAF) of TP53 mutations varied from 3% to 97% with 14 mutations showing 〈 10% VAFs. Showing a significant correlation with mutated TP53 (Odds ratio 20: 95%CI 6.4-61, P 〈 0.001), loss of heterozygosity affecting the TP53 locus was observed in 11 (37%) cases and caused by del(17p) in most cases (n=10). We next evaluated clinical features of TP53-mutated cases. TP53 was most frequently mutated in Hypodiploid ALL (33% n=3), followed by MLL rearrangement (12% n=4), IGH-DUX4 (9% n=5), Others (3% n=8), TCF3-PBX1 (2% n=2), Hyperdiploid (2% n=6), and ETV6-RUNX1 (n=2 0.9%). TP53 mutations were not associated with age or white blood cell count at diagnosis. However, significantly more patients were categorized into National Cancer Institute (NCI) high risk (HR) category (Odds ratio 2.4: 95%CI 1.1-5.3, P = 0.03) and TP53 mutation was associated with a significantly shorter overall survival (OS) among NCI-HR patients (n = 16; HR for death, 6.3; 95% CI, 3.1-13; P 〈 0.001). Five-year OS of NCI-HR patients with TP53 mutations was 44%, suggesting that early treatment intensification or alternative treatment strategies are warranted for these patients. TP53 mutations were also associated with a shorter OS in MLL rearrangement and IGH-DUX4 ALL. Particularly, 67% (n=4/6) of cases with any cause of death harbored TP53 mutation in IGH-DUX4 ALL. In contrast, TP53 mutation was not associated with shorter overall survival in NCI-SR cases. In Hyperdiploid ALL, 5 out of 6 cases with TP53 mutations were categorized into the NCI-SR category and were all alive. Prognostic impact of TP53 mutation was also investigated using recursive partitioning to generate a hierarchical prognostic model for OS by incorporating genetic subgroups and the NCI risk criteria. This model also demonstrated that the NCI risk criteria was the most important prognostic variable and TP53 mutation was used for stratification of patients only in the NCI-HR category. Conclusion TP53 mutations at diagnosis are common in Hypodiploid ALL and also found in a substantial fraction of MLL rearrangement and IGH-DUX4 ALL, where the mutations predict a poor prognosis. TP53 mutation is also found in NCI-SR cases but may not be associated with poor prognosis. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-115617
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 5
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    TAL1 and MYB Abnormalities in Childhood T-Cell Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 2628-2628
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2628-2628
    Abstract: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Although gene fusions generated through chromosomal translocations, deletions, and inversions are the most frequent genetic abnormalities detected in other types of leukemia, recurrent gene fusions except for SIL-TAL1 have been poorly defined in T-ALL. To discover driver mutations or fusion genes, which involved in the pathogenesis of childhood T-ALL and to identify novel prognostic markers of childhood T-ALL, we performed whole-exome sequencing (WES) and transcriptome sequencing (WTS) in 31 and 46 cases, respectively. We also performed SNP array karyotyping in 46 cases. To detect somatic mutations or fusion transcripts, we used our pipeline "Genomon-exome" and "Genomon-fusion" algorithm. Subsequently, somatic mutations were validated using deep amplicon sequencing. Candidate fusion transcripts were validated by reverse - transcription polymerase-chain-reaction and Sanger sequencing.Recurrent mutations observed in more than 3 cases were detected in NOTCH1 (n = 18, 58%), FBXW7 (n = 7, 23%), PHF6 (n = 5, 16%), GATA3 (n = 4, 13%), MYB (n = 3, 10%), and NRAS (n = 3, 10%), respectively. We identified previously known fusion genes, such as MLL-ENL (n = 2), CALM-AF10 (n = 2), NUP214-ABL1 (n = 1) and FGFROP1-FGFR1 (n = 1). MLL-ENL is one of the frequent translocation in infant multilineage leukemia, but also reported in non-infant B cell precursor ALL and T-ALL. FGFR1OP is ubiquitously expressed, and the predicted chimeric FGFR1OP-FGFR1 protein contains the catalytic domain of FGFR1. It is thought to promote hematopoietic stem cell proliferation and leukemogenesis through a constitutive phosphorylation and activation of the downstream pathway of FGFR1. CALM-AF10 leukemia is reported to increase HOXA cluster gene transcription, we could also confirm elevated HOXA genes expression by FPKM value. Four SIL-TAL1 fusions were detected in our cohort. Recently, a novel mutation in TAL1 enhancer region which introduce de novo MYB biding site has been reported. Since this abnormality lead high expression of TAL1, we also analyzed expression data obtained from WTS. Among 46 specimens, 19 samples showed high expression of TAL1 (FPKM value ≥5). In those cases, 4 cases had SIL-TAL1 fusions (8%), and 3 cases (6%) had insertions in enhancer region of TAL1. Subsequent analysis using Gene Set Enrich Analysis (GSEA) between TAL1 high and low expression samples revealed that "LEE_EARLY_T_LYMPHOCYTE_UP" was enriched in TAL1 high expression samples (Enrichment score = 0.73, FDR = 0.073). This gene set includes genes up-regulated at early stages of progenitor T lymphocyte maturation compared to the late stages, and MYB was included in this gene set. Intriguingly, MYB mutation samples were not represented TAL1 high expression. TAL1 related rearrangement or enhancer insertion was not detected in the rest of 12 cases with TAL1 high expression, suggesting that other mechanisms of TAL1 high expression might be exist. In conclusion, although NOTCH1 and FBXW7 mutations were relatively frequently detected in our series, we also found recurrent MYB mutations. SIL-TAL1 was known as most frequent rearrangement, TAL1 enhancer insertions were also frequent in TAL1 overexpressed samples. TAL1 enhancer insertion and MYB mutation was exclusive, suggesting that TAL1 and MYB have a key role in childhood T-ALL. Consistent with other reports, frequent translocations were not observed in T-ALL, suggesting the genetic differences between T-ALL and other hematological malignancies. Further studies will be necessary to unravel oncogenic mechanisms that implicated in new therapeutic strategy for childhood T-ALL. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.2628.2628
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 6
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    Identifications of Highly Aggressive Phenotype with SPI1 Overexpression in Pediatric T Cell Acute Lymphoblastic Leukemia/Lymphoma
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 909-909
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 909-909
    Abstract: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL), arising from the malignant transformation of hematopoietic progenitors primed toward T cell development, as result of a multistep oncogenic process. However, since the prognostic significance of these genetic alterations in pediatric T-ALL is not clear, genetic basis which contributes aggressive phenotype or progression of pediatric T-ALL is still to be elucidated. Therefore, to discover driver genetic events, which involved in the aggressive phenotype of pediatric T-ALL and to identify it's novel prognostic markers, we performed integrated genetic analysis in a large cohort of T-ALL case. Our cohorts included samples from Tokyo Children's Cancer Study Group (TCCSG) and Japan Association of Childhood Leukemia Study (JACLS). Whole transcriptome sequencing (WTS) was performed in 123 cases. Representative recurrent fusion genes were as follows, SIL-TAL1 (n=25), MLL-ENL (n=5), PICALM-MLLT10 (n=5), and NUP214-ABL1 (n=2). Intriguingly, novel recurrent in-frame SPI1 fusions (STMN1-SPI1 n=2; TCF7-SPI1 n=5) were detected, and RT-PCR analysis in additional 60 cases revealed other 2 TCF7-SPI1 fusions. Thus, SPI1 fusions accounted for 4% of pediatric T-ALL/LBL. Expression data of WTS revealed cases with SPI1 fusion showed significantly higher expression of SPI1 compared to cases without SPI1 fusion, implicating that aberrant high expression of SPI1 involved in leukemogenesis. To address the functional activities of SPI1 fusions, we performed luciferase assay using the reporter vector contained the CSF1 promoter region with SPI1 binding site. Transient transfection of Hela cells with the SPI1 fusions expression vectors as well as the wild type SPI1 expression vector showed strikingly high levels of transcription of the reporter genes, as compared to transfection with the empty expression vector, indicating that both SPI1 fusions have transcriptional activities. Next, to analyze the leukemogenic potential of SPI1 fusions in vitro, we transduced fusions cDNA into mouse double negative T-cells. Since p16(CDKN2A) is frequently silenced in T-ALL, we also used p16 null double negative T-cells. Both wild-type and p16 null double negative T-cells expressing SPI1 fusions showed increased cell proliferation compared to the MOCK cells. We further evaluated the impact of SPI1 fusions on T cells differentiation. TCF7-SPI1 or MOCK vector was transduced mononuclear cells isolated from mouse bone marrow. These cells were cultured under stimulating factors, such as IL6 and TPO for 3 days, and then transplanted into the irradiated mouse. Subsequently, 6 week after transplantation, FACS analysis was performed. Of interest, significantly high population of cells expressing TCF7-SPI1 was observed in the immature single positive stage, implicating that their differentiation was impaired at the pre-T cell stage. These results indicate that novel SPI1 fusions have a potential leukemogenic effect in pediatric T-ALL. We defined SPI1 overexpression cases as outliers of SPI1 expression, resulting in extremely poor prognosis (log-rank p = 1.9 ×10-6). Of note, significant poor outcome was confirmed by univariate and multivariate analysis in cases with SPI1 overexpression cases (log-rank p = 9.3 ×10-6, and p = 2.0 ×10-6, respectively). In conclusion, SPI1 fusions expressing cells expanded and they remained at an immature stage, implicating a potential leukemogenic activity of these fusions. Not only the cases with SPI1 fusions, but also the cases with high SPI1 expression without fusions showed extremely poor prognosis, suggesting the prognostic value of aberrant SPI1 expression in pediatric T-ALL. Although it remains unclear, why cases with SPI1 fusions/high SPI1 expression have a poor prognosis, our results indicate that these cases are genetically distinct subgroup from other pediatric T-ALL. Disclosures Kataoka: Kyowa Hakko Kirin: Honoraria; Yakult: Honoraria; Boehringer Ingelheim: Honoraria. Ogawa:Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.909.909
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 7
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    MLL-AF9 Positive Acute Myeloid Leukemia Cells Are Sensitive To All-Trans Retinoic Acid
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3827-3827
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3827-3827
    Abstract: Among the subtypes of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) responds dramatically to differentiation therapy with all-trans retinoic acid (ATRA). But, ATRA is not sufficient to induce differentiation in non-APL AML. Herein, we first evaluated whether MLL fusion partners, such as MLL-AF9 and MLL-AF4/AF5q31, affect the sensitivity of ATRA in human and murine MLL fusion positive AML cell lines. In addition, we also assessed the level of H3K4me2 modification for the RARα gene in human AML cell lines, and whether the LSD1 inhibitor affected the ATRA-resistant MLLfusion positive AML cell lines. Methods Three human AML cell lines with MLL fusion (THP1 and MOLM13 expressing MLL-AF9, and KOCL48 expressing MLL-AF4) and two murine leukemic cell lines derived from murine Lin- hematopoietic progenitors transduced by retroviral vector expressing MLL fusion genes, such as MLL-AF9 and MLL-AF5q31 were used in this study. To test the sensitivity of ATRA, all cell lines were treated with 1 μM ATRA for three days. Monocytic differentiation was assessed by morphological analysis, NBT reduction test and flow cytometric analysis (FCM) of CD11b expression. Quantitative RT-PCR (qRT-PCR) analysis and western blotting was carried out to measure the RARα, C/EBPα, C/EBPε, and PU.1 expressions. Cytotoxicity assay was performed to determine the IC50 of ATRA in these cell lines and whether ATRA could decrease the IC50 of cytarabine in MLL-AF9positive cells by using WST assays. Chromatin immunoprecipitation (ChIP) assay was performed to determine the value of H3K4me2 status using RARα-specific primers. To determine whether tranylcypromine (TCP), which is a nonreversible LSD1 inhibitor, could reactivate ATRA sensitivity, we treated KOCL48 with 10 μM TCP and 1μM ATRA. Results We first determined that morphological changes characteristic of monocytic differentiation, CD11b expression and NBT reduction are more readily induced by ATRA in human and murine MLL-AF9 positive cells than MLL-AF4/AF5q31 positive cells. The NBT reduction percentage was 12.5±3.77 in THP1, 13.1±2.02 in MOLM13, but 7.00±2.64 in KOCL48 cells (p 〈 0.05). The ATRA treatment also induced growth inhibition and increased gene expression related to monocytic differentiation through retinoic acid (RA) pathway, more efficiency in MLL-AF9 positive cells than MLL-AF4/AF5q31 cells. The IC50 of ATRA for THP1, MOLM13 and murine MLL-AF9 cells was 3.85, 1.24 and 1.95 μM, but over 10 μM for KOCL48 and murine MLL-AF5q31 cells. Furthermore, qRT-PCR and western blot revealed that ATRA increased expression level of RARα, C/EBPα, C/EBPε, and PU.1 in MLL-AF9 positive cells, but not in MLL-AF4/AF5q31 positive cells. Collectively, RA pathway is more impaired in MLL-AF4/AF5q31 positive cells than MLL-AF9 positive cells. In addition, the increase in RARα, C/EBPα, C/EBPε, and PU.1 mRNA expressions were observed in two primary MLL-AF9 positive AML cells treated with ATRA. Next, we also carried out ChIP assay and the H3K4me2/ H3 on the RARα promoter in MLL-AF9 positive cells were higher than MLL-AF4 positive cell. Furthermore, ATRA and TCP combination treatment in KOCL48 induced morphological changes, CD11b expression, and increased the expression level of RARα, C/EBPα, C/EBPε, and PU.1, suggesting that inhibition of LSD1 restores ATRA sensitivity. Finally, ATRA in combination with cytarabine treatment in MLL-AF9 positive cells enhanced cytarabine sensitivity: the IC50 of cytarabine in THP1, MOLM13, and murine MLL-AF9cells was 4.18, 0.04, and0.065 μM without ATRA and 0.13, 0.0005, and 0.015 μM with ATRA, respectively. Conclusions Our data demonstrated that RA pathway was more profoundly impaired in MLL-AF4/AF5q31 positive cells than MLL-AF9 positive cells, suggesting type of MLL fusion protein contributes inactivation of RA pathway. Our data also identified the sensitivity of ATRA was correlated with the ratio of H3K4me2/ H3 on the RARα promoter, and TCP restore the sensitivity of ATRA in KOCL48, suggesting the decrease of the H3K4me2/H3 plays a role in inactivation of RA pathway. Additionally, we revealed that synergistic antileukemic activity of ATRA in combination with cytarabine in MLL-AF9 positive cells. Therefore, ATRA in combination with cytarabine might be novel therapeutic option for the ATRA sensitive AML cells, especially for MLL-AF9 positive cells. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.3827.3827
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 8
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    LSD1 Inhibitor Activates Retinoic Acid Pathway in MLL Fusion Positive Acute Myeloid Leukemia
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1345-1345
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1345-1345
    Abstract: Abstract 1345 Background: Among the subtypes of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) responds dramatically to differentiation therapy with all-trans retinoic acid (ATRA). However, ATRA is not sufficient to induce differentiation in non-APL AML. Although the molecular basis for the poor response of non-APL AML to ATRA was poorly understood, Lysine-specific demethylase 1 (LSD1), the histone demetylase, was found to inhibit the retinoic acid pathway by chromatin modification through H3K4 demethylation, resulting in silencing of gene expression targeted by retinoic acid. Herein, we first evaluated whether MLL fusion partners, such as MLL-AF9 and MLL-AF4/AF5q31, affect the sensitivity of ATRA in human and murine MLL fusion positive AML cells, which is one of the most aggressive pediatric AML. In addition, we also assess whether the LSD1 inhibitor affects the ATRA sensitivity in MLL fusion positive AML cells. Methods: Three human AML cell lines with MLL fusion (THP-1 and MOLM-13 expressing MLL-AF9, and KOCL48 expressing MLL-AF4) and two murine leukemic cell lines derived from murine Lin- hematopoietic progenitors transduced by retroviral vector expressing MLL fusion genes, such as MLL-AF9 and MLL-AF5q31 were used in this study. To test the sensitivity of ATRA, all cell lines were treated with 1 μM ATRA for three days. Cell growth was analyzed by counting nuclei using a Coulter counter. Monocytic differentiation was assessed by morphological analysis, NBT reduction test and flow cytometric analysis (FCM) of CD11b expression. FCM analysis was also carried out to evaluate cell cycle and annexin V assay. Quantitative RT-PCR (qRT-PCR) analysis and western blotting was carried out to measure the RARα, C/EBPα, C/EBPε, and PU.1 expressions. To determine whether Tranylcypromine (TCP), which is a nonreversible LSD1 inhibitor, could decrease the IC50 of ATRA in MLL-AF4/AF5q31 positive cells, KOCL48 and murine MLL-AF5q31 expressing cells were treated with 0μM or 10μM TCP and titrating doses of ATRA (ranging from 0μM to 10μM). After three days, cell count was analyzed by counting nuclei using a Coulter counter to evaluate IC50 of ATRA in each cell lines. Results: We first determined that morphological changes characteristic of monocytic differentiation, CD11b expression and NBT reduction are more readily induced by ATRA in human and murine MLL-AF9 positive cells than human and murine MLL-AF4/AF5q31 positive cells The NBT reduction percentage was 17.6±1.69 in THP-1, but 2.7±1.2 in KOCL48 cells (p 〈 0.01). The ATRA treatment also induced growth inhibition accompanied with G0/G1 arrest and apoptosis more efficiency in MLL-AF9 positive cells than MLL-AF4/AF5q31 cells. The IC50 of ATRA for THP-1 cells was 0.21±0.04 μM, but 5.31±1.50 μM for KOCL48 cells (p 〈 0.01) The percentage of cells arrested in G0/G1 phase and Annexin/PI positive cells were 84% and 17.8% in THP-1 but 40% and 4.8% in KOCL48, respectively. Furthermore, qRT-PCR analysis and western blot analysis revealed that ATRA increased expression level of RARα, C/EBPα, C/EBPε, and PU.1, which is involved in monocytic differentiation through retinoic acid pathway, in MLL-AF9 positive cells, but not in MLL-AF4/AF5q31 positive cells. Collectively, retinoic acid pathway is more impaired in MLL-AF4/AF5q31 positive cells than MLL-AF9 positive cells. Next, we also determined that ATRA and TCP combination treatment suppressed cell growth and decreased the IC50 of ATRA in KOCL48 and murine MLL-AF5q31 expressing cells (IC50 of ATRA: 0.20±0.10 μM and 0.20±0.09 μM with TCP, vs 5.5±3.2 μM and over 10 μM without TCP, p 〈 0.05), accompanied with morphological changes and CD11b expression, suggesting that inhibition of LSD1 restores ATRA sensitivity in both cell lines. Conclusions: Our data demonstrate that retinoic acid pathway was more profoundly impaired in MLL-AF4/AF5q31 positive cell than MLL-AF9 positive cells, suggesting MLL-AF4/AF5q31 contributes inactivation of retinoic acid pathway. Our data also demonstrate TCP restore the sensitivity of ATRA in ATRA-resistant MLL-AF4/AF5q31 positive cell lines, suggesting LSD1 plays a major role in inactivation of retinoic acid pathway in MLL-AF4/AF5q31 positive cells. Therefore, LSD1 inhibitor might be important novel therapeutic option for differentiation therapy of MLL-fusion positive AML, especially for ATRA resistant MLL-AF4/AF5q31 positive cells. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1345.1345
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 9
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    Negative CD19 Expression Is Associated with Inferior Relapse-Free Survival in RUNX1-RUNX1T1-Positive Acute Myeloid Leukemia; The Japanese Pediatric Leukemia/Lymphoma Study Group Experience from the AML-05 Study
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2810-2810
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2810-2810
    Abstract: Background: Acute myeloid leukemia (AML) with RUNX1-RUNX1T1 and CBFB-MYH11 have been recognized as core-binding factor (CBF) AML accounting for 25% of the pediatric AML patients. CBF-AML patients have been considered to have a good prognosis, but 30 - 50 % of the RUNX1-RUNX1T1-positive AML patients experience relapse. This finding suggests that some population of them have risk factors associated with poor outcome. Previous studies revealed that KIT activating mutation as a predictor of poor outcome. In addition, previous studies of relatively small number of patients also revealed that CD56 positivity or CD19 negativity were also poor prognostic factors. However, the relationship between KIT activating mutation and specific pattern of cell surface antigens has not been fully investigated. Aim and methods: We performed a retrospective analysis of RUNX1-RUNX1T1-positive AML patients treated in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol to determine risk factors of relapse using the integration of data including pattern of cell surface markers on leukemic cell at diagnosis, genetic abnormalities, and clinical characteristics. Flow cytometric analysis of immunophenotyping was performed in the central laboratories using same panel of antibodies. Conventional cytogenetic analysis using G-banding was performed as part of the routine work-up. Molecular study using quantitative RT-PCR for the detection of RUNX1-RUNX1T1 and PCR for the detection of FLT3-ITD was also performed as part of the routine work-up. Screening of mutation of 8 genes, such as NRAS, KRAS, KIT, WT1, C/EBPA, ASXL1, ASXL2, and CSF3R, was performed by genomic PCR and Sanger sequencing. A total of 106 AML patients enrolled in the JPLSG AML-05 study were RUNX1-RUNX1T1-positive AML, but we could not obtain the data of cell surface marker in 6 of them. Thus, we analyzed 100/106 (94.3%) patients with RUNX1-RUNX1T1-positive AML. Statistical analysis was performed by Kaplan-Meier method with log-rank test. A Cox proportional hazards model was used to determine risk factors for survival and relapse. Results are reported as adjusted odds ratios with 95% confidence intervals. Statistical significance was set at p 〈 0.05. Results: In entire study population, 8 of the 100 patients died and 24 of the 100 patients experienced relapse, respectively. The 3-year overall survival (OS) and relapse-free survival (RFS) rates were 91.7 % (95 % CI; 83.2 - 96.0) and 69.5 % (95 % CI; 59.0 - 77.9), respectively. In terms of genetic analysis, 21 / 100 (21.0%) patients had KIT exon 17 mutation, 11/100 (11.0%) had KIT exon 8 mutation, 6/100 (6%) had KRAS mutation, 16/100 (16%) had NRAS mutation, 2/100 (2%) had C/EBPA mutation, 2/100 (2%) had WT1 mutation, 6/100 (6%) had ASXL1 mutation, 9/100 (9%) had ASXL2 mutation, and 6/100 (6%) had CSF3R mutation. FLT3-ITD was also identified in 3 of the 100 (3%) patients. In terms of cell surface marker expression pattern, CD19 expression was negative in 59 / 100 (59.0%) patients, and CD56 expression was positive in 43 / 100 (43.0%) patients. Patients with KIT exon 17 mutation were significantly accumulated in the CD19 negative (CD19 (-)) population (18 / 59 vs. 3 / 41, p 〈 0.001). Survival analysis revealed that KIT exon 17 mutation and CD19 (-) were associated with inferior 3y-RFS (KIT exon 17 mutation: negative vs positive, 74.6 vs 50%, p 〈 0.01, CD19 expression: positive vs negative, 83.1 vs 59.8 %, p 〈 0.01). On the contrary, CD56 (+) was not associated with poor RFS (positive vs negative, 66.1 vs 74.7%, p=0.15). In addition, CD19 (-) was associated with poor RFS even in the patients without KIT exon 17 mutation (positive vs negative, 85.4 vs 65.2%, p=0.04). Finally, CD19 (-) was the sole significant risk factor of relapse (hazard ratio; 3.09, 95% CI; 1.26 - 7.59, p 〈 0.01) by multivariate analysis. Discussions: This study revealed that CD19 negativity might be a distinct character of poor prognostic subgroup of RUNX1-RUNX1T1-positive AML. On the contrary, CD56 positive was not poor prognostic factor of RUNX1-RUNX1T1-positive AML. Although majority of the patients with KIT exon 17 activating mutation belonged to CD19(-) patients, CD19 (-) patients without KIT exon 17 mutation still showed inferior RFS, suggesting biological difference between CD19 (+) and CD19 (-) RUNX1-RUNX1T1 AML should be investigated. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-115553
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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    Distribution and Clinical Features of NOTCH1 Signaling Activating Alterations in Pediatric T-Cell Acute Lymphoblastic Leukemia (T-ALL)
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4089-4089
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4089-4089
    Abstract: Introduction NOTCH1 and FBXW7 alterations leading to aberrant activation of NOTCH1 signaling, classified into two patterns; ligand-independent activation (LIA) and impaired degradation (ID) of NOTCH1. In general, activation of NOTCH1 axis is a hallmark of T-cell acute lymphoblastic leukemia (T-ALL), though comprehensive studies regarding subclonal mutations inducing NOTCH1 activation are still elusive. In the present study, we explored the clinicopathological relevance of NOTCH1/FBXW7 aberrations considering subclonal alterations. Methods A total of 176 cases with pediatric T-ALL were enrolled in this study. We reanalyzed our previous data of targeted-capture sequencing (n=176) for 158 ALL-related genes/regions and combined with previous expression profiling data based on whole transcriptome sequencing (WTS; n=121). We defined as a subclonal mutation when variant allele frequency was below 0.15 and/or multiple alterations were found within the same pattern of NOTCH1 activation (LIA or ID). All patients were received Berlin-Frankfurt-Münster based chemotherapies with non-minimal residual disease (MRD) based risk stratification, which were mainly offered from the Tokyo Children's Cancer Study Group (TCCSG) and the Japan Association of Childhood Leukemia Study (JACLS). Results In total, we detected aberrations activating NOTCH1 signaling in 81.3% (143/176) of cases including subclonal mutations. Subclonal alterations were observed in 26.7% (n=47). Single nucleotide variations in the heterodimerization domain (HD-SNV) were the most frequent (43.2%; n=76), followed by PEST domain mutations (33.0%; n=58), FBXW7 mutations (26.1%; n=46), non-frameshift indels of NOTCH1 (19.9%; n=35), and in-frame internal duplication known as juxta-membrane expansion (6.3%; n=11). Amplification of NOTCH1 region and 5' NOTCH1 deletion were not detected in our cohort. Both LIA and ID patterns were detected in 43.2% (n=76). Most mutations were mutually exclusive within each LIA and ID pattern. Intriguingly, we detected four (2.3%) internal deletion of NOTCH1 gene (DEL; missing exon 3-27 (DEL3) or 21-27 (DEL21)), three cases (1.7%) of SNV at 3' untranslated region, and two (1.1%) SEC16A-NOTCH1 fusions. These alterations were previously reported to activate NOTCH1 signaling in breast cancer or chronic lymphoblastic leukemia, except for DEL21. We confirmed that DEL21 strongly activates NOTCH1 signaling by luciferase reporter assay (over 100 times compared to wild type NOTCH1). As previously reported in DEL3 and CUTLL cell line, transcripts might initiate at methionine 1737 located within the NOTCH1 transmembrane domain and seem to be sensitive to γ-secretase inhibitors. Analysis of frequency of detected NOTCH1 activating alterations in each previously reported WTS-based cluster (ETP, SPI1, TLX, TAL1-RA, and TAL1-RB) revealed that alterations were frequently detected in TLX (100%; 24/24) and TAL1-RB (95.1%; 39/41), whereas less frequent in TAL1-RA (61.1%; 11/18). In TAL1-RA, all SEC16A-NOTCH1 fusions were observed despite significantly low rate of HD-SNV (11.1%; 2/18). In SPI1 cluster, PEST domain alterations were frequently detected (71.4%; 5/7). Importantly, cases harboring subclonal NOTCH1/FBXW7 alterations showed significantly worse outcome (log-rank P = 0.01), although there was no prognostic difference between cases with and without NOTCH1/FBXW7 mutations. Conclusions We observed NOTCH1 activating alterations in 81.3% of pediatric T-ALL cases and detected rare internal deletion of NOTCH1 gene and NOTCH1 fusions recurrently in T-ALL. Furthermore, the presence of subclonal NOTCH1/FBXW7 mutations might be relevant to unfavorable outcome. Despite several limitations such as non-MRD based treatment, our results might be useful for developing a new anti-NOTCH1 therapeutic strategy for pediatric T-ALL patients. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-111092
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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