The genetics and clinical characteristics of children morphologically diagnosed as acute promyelocytic leukemia

Zhao, Jie; Liang, Jianwei; Xue, Hao; Shen, Shuhong; Chen, Jing; Tang, Yanjing; Yu, Lisha; Liang, Huanhuan; Gu, Long-Jun; Tang, Jingyan; Li, Ben-Shang

doi:10.1038/s41375-018-0338-z

Cited by 50 publications

(62 citation statements)

References 33 publications

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“…Additionally, RARB-related and RARG-related fusion genes have been reported in morphological APL cases recently. [12][13][14][15] As in our case, masked fusion genes could occur in variant APL cases. As conventional analysis alone will not detect all translocations of APL variants.…”

Section: Case Reportsupporting

confidence: 68%

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Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1

Osumi

Watanabe

Okamura

et al. 2019

Genes Chromosomes & Cancer

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Acute promyelocytic leukemia (APL) is cytogenetically characterized by the t(15;17) (q24;q21), although cases without this translocation exist. These cases are referred to as “cryptic” or “masked” translocations. Additionally, fewer than 5% of APL cases have another partner gene fused to the RARA gene. The TBL1XR1‐RARA fusion gene has recently been reported as a novel RARA‐associated fusion gene. We report a case with TBL1XR1‐RARA and a masked translocation that was not detected by conventional tests for RARA‐associated translocations. Three‐year‐old girl was diagnosed with APL based morphological findings, although conventional tests for RARA‐associated chimeric genes were negative. She received all‐trans retinoic acid treatment, but that was not effective. She achieved a complete remission (CR) by conventional multidrug chemotherapy, but had extramedullary relapse 2 years after onset. She underwent cord blood transplantation (CBT) in her second CR and is currently alive. To investigate the underlying pathogenesis of this unique case, we performed whole‐genome sequencing and found a cryptic insertion of RARA gene into the TBL1XR1 gene. The transcript of the chimeric gene, TBL1XR1‐RARA, was confirmed as an in‐frame fusion by RT‐PCR. In conclusion, we found using next‐generation sequencing (NGS) a TBL1XR1‐RARA fusion in a child with variant APL without the classic karyotype. Cryptic insertion could also occur in cases other than APL with PML‐RARA. Variant APL has many variants and NGS analysis should therefore be considered for APL variant cases, even for those without RARA translocation detected by conventional analysis.

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Section: Case Reportsupporting

confidence: 68%

“…[12][13][14][15] As in our case, masked fusion genes could occur in variant APL cases. Additionally, RARB-related and RARG-related fusion genes have been reported in morphological APL cases recently.…”

Section: Case Reportmentioning

confidence: 85%

Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1

Osumi

Watanabe

Okamura

et al. 2019

Genes Chromosomes & Cancer

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“…45 The gene encoding USP9X is often mutated in several solid cancers 46 ; and we and others have also reported its inactivating mutations in acute promyelocytic leukemia. 47,48 All SRSF2 mutant samples in our cohort exhibited usage of a non-canonical splice site leading to transcripts with an in-frame deletion of 198 amino acid residues, which partly encode for the ubiquitin carboxyl-terminal hydrolases (UCH) domain of USP9X. Notably, mis-splicing of USP24, a deubiquitinase closely related to USP9X, 49 was also detected in SRSF2 del samples in our cohort.…”

Section: Gene Expression Profiling Reveals Dysregulated Heme Metabomentioning

confidence: 70%

Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes

Madan

Zhou

et al. 2019

American J Hematol

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Myelodysplastic syndromes (MDS) are characterized by recurrent somatic alterations often affecting components of RNA splicing machinery. Mutations of splice factors SF3B1, SRSF2, ZRSR2 and U2AF1 occur in >50% of MDS. To assess the impact of spliceosome mutations on splicing and to identify common pathways/genes affected by distinct mutations, we performed RNA-sequencing of MDS bone marrow samples harboring spliceosome mutations (including hotspot alterations of SF3B1, SRSF2 and

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“…[3][4][5] Patients with CPSF6-RARG, a very rare occult fusion gene by inv(12q13;12q15), are difficult to diagnose; therefore, they are difficult to treat effectively. [6][7][8] In this study, we report a case of AML, morphologically and immunophenotypically resembling APL, and carrying a novel CPSF6-RARG variant that was generated by the fusion of exon 5 of CPSF6, and exon 1 of RARG. Complete remission was achieved after treating the patient with a homoharringtonine (HA) and cytarabine chemotherapy regimen but not with differentiation-inducing therapy or conventional anthracycline plus cytarabine chemotherapy.…”

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confidence: 99%

“…With the application of secondgeneration sequencing technology in the clinical diagnosis, four patients were reported with CPSF6-RARG, and one with RARG-CPSF6. [6][7][8][9] All of the patients were morphologically diagnosed with APL, suggesting that their disease had a similar pathogenesis to that of APL. However, none of the patients with CPSF6-RARG or RARG-CPSF6 experienced a response to ATRA and ATO, suggesting that it is a novel subtype of AML.…”

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confidence: 99%

Acute myeloid leukemia with a novel CPSF6‐RARG variant is sensitive to homoharringtonine and cytarabine chemotherapy

et al. 2019

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of detection) did not identify an aberrant clonal plasma cell population in this patient.We conclude that for select patients with clinical features of systemic AL amyloidosis (ie, heart failure with preserved ejection fraction, proteinuria, unexplained hepatomegaly, and axonal demyelinating peripheral neuropathy), the absence of monoclonal gammopathy should not deter aspiration of subcutaneous fat and/or tissue biopsy of the affected organ. Only histopathological analysis for Congophilia and accurate precursor protein typing can lead to diagnosis in some cases. Moreover, it is important to distinguish these systemic cases from localized AL amyloidosis, which does not require systemic chemotherapy.The authors declare no competing conflicts of interest. AUTHOR CONTRIBUTIONSAS collected and analyzed data, and wrote the manuscript in consultation with YK, DJM and JMS; VS edited and revised the final version.

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The genetics and clinical characteristics of children morphologically diagnosed as acute promyelocytic leukemia

Cited by 50 publications

References 33 publications

Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1

Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1

Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes

Acute myeloid leukemia with a novel CPSF6‐RARG variant is sensitive to homoharringtonine and cytarabine chemotherapy

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