The short isoform of the long‐type <i><scp>PML</scp>‐<scp>RARA</scp></i> fusion gene in acute promyelocytic leukaemia lacks sensitivity to all‐trans‐retinoic acid

Tan, Yanhong; Bian, Sicheng; Xu, Zhifang; Chen, Xiuhua; Qi, Xiling; Ren, Fanggang; Li, Li; Guo, Haixiu; Xu, Aining; Zhang, Linlin; Wang, Hongwei

doi:10.1111/bjh.12362

Cited by 11 publications

(10 citation statements)

References 11 publications

(12 reference statements)

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“…For example, PML‐RARA has several break points, and the different variants may influence prognosis . Even when the same break points are present, there are isoform variants with prognostic implications . Moreover, recent studies have identified several fusion genes, including NUP98‐NSD1 and CBFA2T3‐GLIS2 , which are associated with AML prognosis .…”

Section: Discussionmentioning

confidence: 99%

“…15 Even when the same break points are present, there are isoform variants with prognostic implications. 16 Moreover, recent studies have identified several fusion genes, including NUP98-NSD1 and CBFA2T3-GLIS2, which are associated with AML prognosis. [17][18][19] Therefore, we intend to develop and implement the present multiplex quantitative RT-PCR strategy to enable improved risk-stratification for patients with pediatric AML.…”

Section: Discussionmentioning

confidence: 99%

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Multiplex fusion gene testing in pediatric acute myeloid leukemia

Iijima-Yamashita

Matsuo

Yamada

et al. 2018

Pediatrics International

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Background: Gene abnormalities, particularly chromosome rearrangements generating gene fusion, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification, but the results are not always consistent with those of reverse transcriptionpolymerase chain reaction (RT-PCR), and more accurate and rapid methods are required.Methods: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and from acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation. Multiplex quantitative RT-PCR was performed to detect eight important fusion genes: MLL-ELL, MLL-AF6(MLLT4), FUS(TLS)-ERG, NUP98-HOXA9, and PML-RARA.Results: Fusion genes were detected in 207 (46.2%) of the 448 AML-05 patient samples. After exclusion of two samples with PML-RARA, no chromosomal abnormalities were identified on karyotyping in 19 of 205 patients (9.3%) positive for fusion genes on RT-PCR. Fusion genes were confirmed on fluorescence in situ hybridization (FISH) in 11 of these 19 patients. In contrast, fusion genes were detected in 37 of 39 patients (94.9%) from the AML-P05 study, and 33 of these results were consistent with the karyotyping. There were discrepancies in four patients (10.8%), three with normal karyotypes and one in whom karyotyping was not possible. All four of these patients were PML-RARA positive on FISH.Conclusions: Multiplex quantitative RT-PCR-based fusion gene screening may be effective for diagnosis of pediatric AML.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multiplex fusion gene testing in pediatric acute myeloid leukemia

Iijima-Yamashita

Matsuo

Yamada

et al. 2018

Pediatrics International

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“…The incidence of ider(17) (q10)t(15;17) in our center is 1.89%, which is consistent with previous report. 6 Although previous studies 11 , 21 reported that the ider(17q)(q10)t(15;17) had a slightly higher frequency in APL patients with PML-RARA bcr1 subtype, which might be related to delayed CR and lower sensitivity to ATRA treatment, we found no significant correlation between ider(17) (q10)t(15;17) and 3 isoforms of PML-RARA gene (bcr1, bcr 2 and bcr3 subtypes) in our center, which may be caused by the rarity of ider(17) (q10)t(15;17) since we only have 12 ider(17) (q10)t(15;17) positive cases until now.…”

Section: Discussionmentioning

confidence: 90%

A Pediatric Acute Promyelocytic Leukemia With a Rare Karyotype of ider(17)(q10)t(15;17) and Favorable Outcome

Wang

Liang

et al. 2015

Medicine

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Acute promyelocytic leukemia (APL) is a specific malignant hematological disorder with a diagnostic hallmark of chromosome translocation t(15;17)(q22;q21). As a very rare secondary cytogenetic aberration in pediatric APL, ider(17q) (q10)t(15;17) was suggested to be a poor prognostic factor based on previous case reports.Here, we report a pediatric APL case with a rare karyotype of ider(17)(q10)t(15;17). Bone marrow aspiration, immunophenotyping, molecular biology, cytogenetic, and fluorescence in situ hybridization (FISH) analyses were performed at initial diagnosis and during the treatment.A 6-year-old boy was brought to our hospital with the chief complaint of bleeding gums twice and intermittent fever for 3 days in January 2013. He was diagnosed as low-risk APL according to the 2012 NCCN guideline on APL, with the expression of PML-RARA (bcr3 subtype) and the karyotype of 46,XY, der(15)t(15;17)(q22;q21),ider(17)(q10)t(15;17), which was further verified by FISH. The patient was treated through combination all-trans retinoic acid (ATRA) and arsenic with daunorubicin according to the 2012 NCCN guideline for APL. Continuous hematological completed remission (HCR) and major molecular remission (MMR) were achieved with normal karyotype for >28 months after induction chemotherapy.Different from previously reported cases, this pediatric APL patient with ider(17)(q10)t(15;17) displays favorable clinical outcomes, which might be related to the low-risk classification and arsenic treatment during the treatment. It suggests that ider(17)(q10)t(15;17) may not be the sole determinant for worse outcomes in pediatric APL and implies that more contributed factors should be considered for pediatric APL prognosis.

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“…Published results on APL cell lines also suggest a possible association between the splicing variants of the PML-RARA fusion gene and the therapeutic response to ATRA [ 57 ]. These variants resulted from the alternative splicing of the PML sequence, which contains heterogeneous breakpoint cluster regions (bcrs) at three different sites (Fig.…”

Section: Predictive Biomarkers Of Retinoid Resistancementioning

confidence: 99%

“…Sequencing analysis of the PML-RARA gene in a cohort of 79 APL patients showed that the L-type fusion transcript resulting from the alternative splicing was present in three isoforms. One of these isoforms, the E5(−)E6(−) isoform with exons 5 and 6 deleted, is associated with the ATRA-resistant phenotype [ 57 ]. A subsequent localization study reported that the E5(−)E6(−) protein was detected in the cytoplasm only, whereas the other two isoforms were distributed throughout the nucleus and cytoplasm.…”

Section: Predictive Biomarkers Of Retinoid Resistancementioning

confidence: 99%

Traffic lights for retinoids in oncology: molecular markers of retinoid resistance and sensitivity and their use in the management of cancer differentiation therapy

et al. 2018

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For decades, retinoids and their synthetic derivatives have been well established anticancer treatments due to their ability to regulate cell growth and induce cell differentiation and apoptosis. Many studies have reported the promising role of retinoids in attaining better outcomes for adult or pediatric patients suffering from several types of cancer, especially acute myeloid leukemia and neuroblastoma. However, even this promising differentiation therapy has some limitations: retinoid toxicity and intrinsic or acquired resistance have been observed in many patients. Therefore, the identification of molecular markers that predict the therapeutic response to retinoid treatment is undoubtedly important for retinoid use in clinical practice. The purpose of this review is to summarize the current knowledge on candidate markers, including both genetic alterations and protein markers, for retinoid resistance and sensitivity in human malignancies.

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The short isoform of the long‐type PML‐RARA fusion gene in acute promyelocytic leukaemia lacks sensitivity to all‐trans‐retinoic acid

Cited by 11 publications

References 11 publications

Multiplex fusion gene testing in pediatric acute myeloid leukemia

Multiplex fusion gene testing in pediatric acute myeloid leukemia

A Pediatric Acute Promyelocytic Leukemia With a Rare Karyotype of ider(17)(q10)t(15;17) and Favorable Outcome

Traffic lights for retinoids in oncology: molecular markers of retinoid resistance and sensitivity and their use in the management of cancer differentiation therapy

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