Sequential Approach to Improve the Molecular Classification of Childhood Acute Lymphoblastic Leukemia

Yu, Chih-Hsiang; Wu, Gang; Chang, Chia‐Hao; Jou, Shiann‐Tarng; Lu, Meng‐Yao; Lin, Kai‐Hsin; Chen, Shu-Huey; Wu, Kang‐Hsi; Huang, Fang‐Liang; Cheng, Chao‐Neng; Chang, Hong-Yeh; Hedges, Dale J.; Wang, Jinn-Li; Yen, Hsiu Ju; Li, Meng-Ju; Chou, Shu‐Wei; Hung, Chia-Liang; Lin, Ze-Shiang; Lin, Chien‐Yu; Chen, Hsuan‐Yu; Ni, Yu-Ling; Hsu, Yin-Chen; Lin, Dong‐Tsamn; Lin, Shu‐Wha; Yang, Jun J.; Pui, Ching‐Hon; Yu, Sung‐Liang; Yang, Yung‐Li

doi:10.1016/j.jmoldx.2022.08.001

Cited by 5 publications

(10 citation statements)

References 53 publications

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“…Moreover, to complement MRD‐guided risk stratification, we implemented RNA‐seq subtype classification as well as a risk stratification workflow within our successor TPOG‐ALL trial. We conclude that this sequential approach can enable diagnosis under the guidance of national insurance restrictions 31 . However, this study had one major limitation.…”

Section: Discussionmentioning

confidence: 79%

“…We conclude that this sequential approach can enable diagnosis under the guidance of national insurance restrictions. 31 However, this study had one major limitation. Except for patients with ETV6-RUNX1 or high hyperdiploidy, the enrolled number of cases for each of the novel subtypes was small, and thus it is difficult to reach definitive conclusions for subgroups with few case numbers.…”

Section: Prognostic Value Of the Mrd Level On Days 15 And 42mentioning

confidence: 93%

“…Samples without identified genetic alterations were subjected to RNA sequencing (RNA‐seq) analysis. The details of the procedural flowchart and RNA‐seq analysis have been described elsewhere 31,34 …”

Section: Methodsmentioning

confidence: 99%

“…30 Moreover, a sequential molecular approach including transcriptome analysis was applied to most samples after 2013. 31 In this study, we assessed the relative impact of MRD-guided chemotherapy among different ALL subtypes using data from 295 patients enrolled in TPOG-ALL 2013 protocols.…”

Section: Introductionmentioning

confidence: 99%

“…After 2013, with the introduction of the TPOG‐ALL‐2013 regimen, chemotherapy was adjusted according to the MRD levels on day 15 and at the end of remission induction, in addition to the other parameters mentioned above 30 . Moreover, a sequential molecular approach including transcriptome analysis was applied to most samples after 2013 31 . In this study, we assessed the relative impact of MRD‐guided chemotherapy among different ALL subtypes using data from 295 patients enrolled in TPOG‐ALL 2013 protocols.…”

Section: Introductionmentioning

confidence: 99%

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Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia

Jou

Su³

et al. 2022

Cancer

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Background This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimal/measurable residual disease (MRD) and recently identified tumor genetic subtypes. Methods Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase–polymerase chain reaction, multiplex ligation‐dependent probe amplification, and RNA‐sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG‐ALL‐2013 study enrolled patients who received MRD‐directed therapy. Results The 5‐year event‐free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD‐guided therapy, those with ETV6‐RUNX1 fusion and high hyperdiploidy had the highest 5‐year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR‐ABL1 ALL. Recently identified subtypes like DUX4‐rearranged, ZNF384‐rearranged, MEF2D‐rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high‐risk or very‐high‐risk subtypes, the TPOG‐ALL‐2013 regimen did not confer significant improvements compared to TPOG‐ALL‐2002, and the outcomes of BCR‐ABL1‐like, MEF2D‐rearranged, and KMT2A‐rearranged ALL subtypes (in addition to those of T‐cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients. Conclusions The TPOG‐ALL‐2013 study yielded outcomes superior to those of patients treated in the preceding TPOG‐ALL‐2002 study. This study provides important data to inform the design of future clinical trials in Taiwan. Plain language summary MRD‐directed therapy improved the outcomes for pediatric ALL, especially standard‐risk patients. Genomic analyses and MRD might be used together for risk‐directed therapy of childhood ALL. Our work provides important data to inform the design of future clinical trials in Taiwan

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Section: Discussionmentioning

confidence: 79%

Section: Prognostic Value Of the Mrd Level On Days 15 And 42mentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia

Jou

Su³

et al. 2022

Cancer

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Terminal deoxynucleotidyl transferase expression in different subtypes of childhood B-cell acute lymphoblastic leukemia

Yu,

Su,

Jou

et al. 2024

Pathology - Research and Practice

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<i>ETV6::ACSL6</i> translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression

Xu,

Tian,

Tai

et al. 2024

haematol

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ETV6::ACSL6 represents a rare genetic aberration in hematopoietic neoplasms and is often associated with severe eosinophilia, which confers an unfavorable prognosis requiring additional anti-inflammatory treatment. However, since the translocation is unlikely to produce a fusion protein, the mechanism of ETV6::ACSL6 action remains unclear. Here, we performed multi-omics analyses of primary leukemia cells and patient-derived xenografts from an acute lymphoblastic leukemia (ALL) patient with ETV6::ACSL6 translocation. We identified a super-enhancer located within the ETV6 gene locus and revealed translocation and activation of the super-enhancer associated with the ETV6::ACSL6 fusion. The translocated super-enhancer exhibited intense interactions with genomic regions adjacent to and distal from the breakpoint at chromosomes 5 and 12, including genes coding inflammatory factors such as IL-3. This led to modulations in DNA methylation, histone modifications, and chromatin structures, triggering transcription of inflammatory factors leading to eosinophilia. Furthermore, the bromodomain and extraterminal domain (BET) inhibitor synergized with standard-of-care drugs for ALL, effectively reducing IL-3 expression and inhibiting ETV6::ACSL6 ALL growth in vitro and in vivo. Overall, our study revealed for the first time a cis-regulatory mechanism of super-enhancer translocation in ETV6::ACSL6 ALL, leading to ALL-accompanying clinical syndrome. These findings may stimulate novel treatment approaches for this challenging ALL subtype.

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Sequential Approach to Improve the Molecular Classification of Childhood Acute Lymphoblastic Leukemia

Cited by 5 publications

References 53 publications

Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia

Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia

Terminal deoxynucleotidyl transferase expression in different subtypes of childhood B-cell acute lymphoblastic leukemia

<i>ETV6::ACSL6</i> translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression

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