Yung-Li Yang

Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia

BACKGROUND Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia

The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3±1.9% in 1997–2001 to 77.4±1.7% in 2002–2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997–2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.

Catheter-Related Bacteremia Caused by Staphylococcus pseudintermedius Refractory to Antibiotic-Lock Therapy in a Hemophilic Child with Dog Exposure

ABSTRACT We describe a case of catheter-related bacteremia due to Staphylococcus pseudintermedius in a child with dog exposure. The organism was confirmed as S. pseudintermedius based on 16S rRNA gene sequence analysis and positive PCR-restriction fragment length polymorphism of the pta gene.

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.

IKZF1 deletions predict a poor prognosis in children with B‐cell progenitor acute lymphoblastic leukemia: A multicenter analysis in Taiwan

Despite current risk‐directed therapy, approximately 15–20% of pediatric patients with acute lymphoblastic leukemia (ALL) have relapses. Recent genome‐wide analyses have identified that an alteration of IKZF1 is associated with very poor outcomes in B‐cell progenitor ALL. In this study, we determined the prognostic significance of IKZF1 deletions in patients with childhood ALL. This study analyzed 242 pediatric B‐cell progenitor ALL patients in Taiwan. We developed a simple yet sensitive multiplex quantitative PCR coupled with capillary electrophoresis to accurately determine the allele dose of IKZF1, and high resolution melting was used for mutation screening for all coding exons of IKZF1. Twenty‐six (10.7%) pediatric B‐cell progenitor ALL patients were found to harbor these deletions. Most of the deletions were broader deletions that encompassed exon 3 to exon 6, consistent with previous reports. Genomic sequencing of IKZF1 was carried out in all cases and no point mutations were identified. Patients with IKZF1 deletions had inferior event‐free survival (P < 0.001), and overall survival (P = 0.0016). The association between IKZF1 deletions and event‐free survival was independent of age, leukocyte count at presentation, and cytogenetic subtype by multivariate Cox analysis (P = 0.003, hazard ratio = 2.45). This study indicates that detection of IKZF1 deletions upon diagnosis of B‐cell progenitor ALL may help to identify patients at risk of treatment failure. IKZF1 deletions could be incorporated as a new high‐risk prognostic factor in future treatment protocols. To the best of our knowledge, this is the first study to examine the poor prognosis of IKZF1 deletions in an Asian population. (Cancer Sci 2011; 102: 1874–1881)

Characterization of Neuroblastic Tumors Using 18F-FDOPA PET

Neuroblastic tumors are childhood neoplasms that possess amino acid decarboxylase (AADC) activity and can theoretically be imaged by 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET, a new diagnostic tool for neuroendocrine tumors. In this study, we explored the accuracy and clinical role of 18F-FDOPA PET in neuroblastic tumors. Methods: From 2008 to 2011, patients with tissue-proven neuroblastic tumors receiving 18F-FDOPA PET at initial diagnosis or during follow-ups were enrolled. The sensitivity and specificity of 18F-FDOPA PET were compared with those of 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy and 18F-FDG PET, using tumor histology as the standard. The maximum standardized uptake value and tumor-to-liver uptake ratio on 18F-FDOPA PET were measured and correlated with AADC messenger RNA level in tumor tissue. Results: Fifty tumors from 34 patients, including 42 neuroblastic tumors and 8 lesions without viable tumor cells, were eligible for analysis. 18F-FDOPA PET successfully detected neuroblastic tumors of different histologic types in various anatomic sites, at a sensitivity of 97.6% (87.4%–99.9%) and a specificity of 87.5% (47.3%–99.7%). In tumors with concomitant studies, 18F-FDOPA PET demonstrated a higher sensitivity than 123I-MIBG scintigraphy (n = 18; P = 0.0455) or 18F-FDG PET (n = 46; P = 0.0455). Among the 18 tumors with concomitant 123I-MIBG scans, 4 tumors with viable cells were 123I-MIBG–negative but were successfully detected by 18F-FDOPA PET. The tumor uptake of 18F-FDOPA significantly correlated with AADC expression (n = 15 nonhepatic tumors; maximum standardized uptake value, P = 0.0002; tumor-to-liver uptake ratio, P < 0.0001). Conclusion: 18F-FDOPA PET showed high sensitivity and specificity in detecting and tracking neuroblastic tumors in this preliminary study with a small cohort of patients and might be complementary to 123I-MIBG scintigraphy and 18F-FDG PET. By correlating with AADC expression, 18F-FDOPA PET might serve as a useful imaging tool for the functional assessment of neuroblastic tumors.

Improved efficacy and tolerability of oral deferasirox by twice-daily dosing for patients with transfusion-dependent β-thalassemia†

Deferasirox is an oral iron‐chelating agent taken once‐daily by patients with transfusion‐dependent iron overload. However, some patients are unresponsive or unable to tolerate once‐daily deferasirox. The current study evaluated whether twice‐daily deferasirox treatment showed increased efficacy or tolerability in unresponsive or intolerant patients.

Expression and prognostic significance of the apoptotic genes BCL2L13, Livin, and CASP8AP2 in childhood acute lymphoblastic leukemia

Improved treatment of childhood acute lymphoblastic leukemia (ALL) depends on the identification of new molecular markers that are able to predict treatment response and clinical outcome. The development of impaired apoptosis in leukemic cells is one factor that may influence their response to treatment. We investigated the expression of three apoptosis related genes, BCL2L13, CASP8AP2, and Livin, as well as their prognostic significance, in a retrospective study of 90 pediatric ALL patients diagnosed between 1996 and 2007 in Taiwan. Univariant analysis revealed that high expression of BCL2L13 was associated with inferior event-free survival and overall survival (p<0.001 and 0.005, respectively). Multivariate analysis for EFS and OS demonstrated that high expression of BCL2L13 was an independent prognostic factor for childhood ALL in this ethnic group.

β-1,4-Galactosyltransferase III enhances invasive phenotypes via β1-integrin and predicts poor prognosis in neuroblastoma.

Purpose: Neuroblastoma (NB) is a neural crest-derived tumor that commonly occurs in childhood. β-1,4-Galactosyltransferase III (B4GALT3) is highly expressed in human fetal brain and is responsible for the generation of poly-N-acetyllactosamine, which plays a critical role in tumor progression. We therefore investigated the expression and role of B4GALT3 in NB. Experimental Design: We examined B4GALT3 expression in tumor specimens from 101 NB patients by immunohistochemistry and analyzed the correlation between B4GALT3 expression and clinicopathologic factors or survival. The functional role of B4GALT3 expression was investigated by overexpression or knockdown of B4GALT3 in NB cells for in vitro and in vivo studies. Results: We found that B4GALT3 expression correlated with advanced clinical stages (P = 0.040), unfavorable Shimada histology (P < 0.001), and lower survival rate (P < 0.001). Multivariate analysis showed that B4GALT3 expression is an independent prognostic factor for poor survival of NB patients. B4GALT3 overexpression increased migration, invasion, and tumor growth of NB cells, whereas B4GALT3 knockdown suppressed the malignant phenotypes of NB cells. Mechanistic investigation showed that B4GALT3-enhanced migration and invasion were significantly suppressed by β1-integrin blocking antibody. Furthermore, B4GALT3 overexpression increased lactosamine glycans on β1-integrin, increased expression of mature β1-integrin via delayed degradation, and enhanced phosphorylation of focal adhesion kinase. Conversely, these properties were decreased by knockdown of B4GALT3 in NB cells. Conclusions: Our findings suggest that B4GALT3 predicts an unfavorable prognosis for NB and may regulate invasive phenotypes through modulating glycosylation, degradation, and signaling of β1-integrin in NB cells. Clin Cancer Res; 19(7); 1705–16. ©2013 AACR.

Pharmacogenomic variations in treatment protocols for childhood acute lymphoblastic leukemia

This retrospective study evaluates the role of pharmacogenomic determinants in the treatment of childhood acute lymphoblastic leukemia (ALL) in the Taiwanese population.