Redundant function of retinoic acid receptor isoforms in leukemogenesis unravels a prominent function of genome topology and architecture in the selection of mutagenic events in cancer

Marinelli, Alessandra; Bossi, Daniela; Pelicci, Pier Giuseppe; Minucci, Saverio

doi:10.1038/leu.2008.205

Cited by 15 publications

(12 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RARG, RARA and RARB are nuclear hormone receptors functioning as ligand-dependent transcriptional activators that interact specifically to modulate transcription of DNA elements, and all have highly conserved DBD and LBD. 8 Fusions and aberrations of RARs contributed to hematopoietic differentiation arrests at promyelocytes stage and constitute the basis for therapeutic response of ATRA-induced differentiation therapy. Although very rare, translocations involving RARB (TBL1XR1-RARB) 9 and RARG (NUP98-RARG, PML-RARG, and CPSF6-RARG) [1][2][3][4] have been reported in APL.…”

Section: Discussionmentioning

confidence: 99%

A novel NPM1-RARG-NPM1 chimeric fusion in acute myeloid leukaemia resembling acute promyelocytic leukaemia but resistant to all-trans retinoic acid and arsenic trioxide

et al. 2019

View full text Add to dashboard Cite

The RARG gene is a member of the nuclear hormone receptor superfamily and shares high homology with RARA and RARB. RARA is involved in translocation with PML in acute promyelocytic leukaemia (APL). Little is known about RARB or RARG rearrangement. RARG fusions were reported in only five APL patients and the partner genes were NUP98, PML and CPSF6. Here, we report NPM1 as a new partner gene of RARG and identify a unique NPM1-RARG-NPM1 chimeric fusion for the first time in an old male with morphological and immunophenotypical features of hypergranular APL but lacking response to all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ) therapy. The structural features of the fusion transcript may account for the clinical resistance of the patient. RARG fusion is rare but recurrent in APL, further investigation in larger cohorts is expected to assess frequency, clinical characteristics and outcomes of RARG-translocation in APL.

show abstract

Section: Discussionmentioning

confidence: 99%

A novel NPM1-RARG-NPM1 chimeric fusion in acute myeloid leukaemia resembling acute promyelocytic leukaemia but resistant to all-trans retinoic acid and arsenic trioxide

et al. 2019

View full text Add to dashboard Cite

show abstract

“…While translocations of RARA, typically PML-RARA, are a genetic hallmark of APL, a small fraction of APL cases lack translocations of RARA. Retinoic acid receptors (RARs) are nuclear hormone receptors which function as ligand-activated transcription factors that interact specifically to modulate transcription DNA elements [159]. RARs include alpha (RARA), beta (RARB), and gamma (RARG) receptor types.…”

Section: Risk-adapted Treatmentmentioning

confidence: 99%

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

Thomas

2019

Oncol Ther

View full text Add to dashboard Cite

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) that is cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARa) genes. Because patients with APL present a tendency for severe bleeding, often resulting in an early fatal course, APL was historically considered to be one of the most fatal forms of acute leukemia. However, therapeutic advances, including anthracyclineand cytarabine-based chemotherapy, have significantly improved the outcomes of APL patients. Due to the further introduction of alltrans retinoic acid (ATRA) and-more recentlythe development of arsenic trioxide (ATO)containing regimens, APL is currently the most curable form of AML in adults. Treatment with these new agents has introduced the concept of cure through targeted therapy. With the advent of revolutionary ATRA-ATO combination therapies, chemotherapy can now be safely omitted from the treatment of low-risk APL patients. In this article, we review the six-decade history of APL, from its initial characterization to the era of chemotherapy-free ATRA-ATO, a model of cancer-targeted therapy.

show abstract

“…3 In addition, inoculated transduced cells expressing PML/ RARG were able to trigger leukemia in vivo in a murine model, displaying morphologic features resembling those obtained with transduction of PML/RARA. 12 In conclusion, we describe here a novel NUP98/RARG gene rearrangement that conferred to leukemic cells acute promyelocytic leukemia-like morphologic and immunophenotypic features. The favorable outcome with a standard 7 ϩ 3 chemotherapy approach, followed by consolidation and intensification with autologous stem-cell transplantation, does not allow us ascertain the sensitivity to ATRA, due to the early discontinuation of the drug in this patient.…”

Section: Org Frommentioning

confidence: 99%

“…Specifically, heterodimers formed by RXRA-RARG are necessary for growth arrest and visceral and primitive endodermal differentiation. 3,12 RARG rearrangements in human leukemia have not been previously described. Recently, La Starza et al 1 reported a case of an adult patient with acute myeloid leukemia of the M2 subtype carrying a t(11;12)(p15;q13) translocation that involved a NUP98 rearrangement with 1 of the following 3 putative candidate genes localized at the translocation break point: RARG, MFSD5, or ESPL1.…”

Section: Org Frommentioning

confidence: 99%

“…RARs are nuclear hormone receptors functioning as ligand-activated transcription factors that interact specifically to modulate transcription of DNA elements. 12 They function as heterodimers with retinoid X receptors. Specifically, heterodimers formed by RXRA-RARG are necessary for growth arrest and visceral and primitive endodermal differentiation.…”

Section: Org Frommentioning

confidence: 99%

See 1 more Smart Citation

A novel NUP98/RARG gene fusion in acute myeloid leukemia resembling acute promyelocytic leukemia

Such¹,

Cervera²,

Valencia³

et al. 2011

Blood

View full text Add to dashboard Cite

Chromosomal translocations in hematological malignancies often result in novel fusion chimeric genes. We report a case of acute myeloid leukemia with a clonal translocation t(11;12)(p15;q13) display- IntroductionChromosomal translocations in hematological malignancies often result in the generation of novel chimeric genes. The nucleoporin 98 gene (NUP98) located at chromosome 11p15 is recurrently involved in a variety of rearrangements in both myeloid and lymphoid malignancies. 1,2 After the first NUP98 rearrangement, Homeobox A9 gene (NUP98/HOXA9), was discovered, more than 20 different fusion partners were reported. 1 Among these partners, other homeobox and non-homeobox genes have been identified as fusion partners of NUP98. We report here a novel NUP98 rearrangement in a patient with acute myeloid leukemia displaying morphologic and immunophenotypic features resembling the classical hypergranular subtype of acute promyelocytic leukemia. This case harbored a novel fusion gene as a result of a chromosomal break point at 12q13 detected in a new 11p15 rearrangement. The gene fused to NUP98 was identified by comparative genomic hybridization (CGH) array as the retinoid acid receptor gamma gene (RARG). RARG is a member of the nuclear receptor superfamily and shares high homology (90%) with RARA and RARB, the other retinoic acid receptors that are involved in retinoid signaling. While an artificial construct has been reported in which RARG is fused to the promyelocytic leukemia gene product (PML), resulting in an oncogenic protein, 3 no cases of human leukemia-bearing RARG fusions have been described. Methods Case reportsThis study was approved by the institutional review board of the Hospital Universitario La Fe. A 35-year-old man was referred to our department with asthenia, mucosal bleeding, spontaneous ecchymoses, and fever. Blood tests showed a hemoglobin level of 6 g/dL, a platelet count of 8 ϫ 10 9 /L, and a white blood cell count of 12 ϫ 10 9 /L with 82% blasts and atypical promyelocytes. Although increased levels of D-dimer were present, the patient did not fulfill the criteria for coagulopathy. 4 Morphologic examination of bone marrow (BM) smears disclosed a monomorphic infiltration by blast cells, 80% hypergranular (atypical promyelocytes, which frequently displayed Auer rods) resembling the hypergranular subtype of acute promyelocytic leukemia (M3) of the French-American-British classification ( Figure 1A-B). The immunophenotype of peripheral blood blasts was positive for CD13, CD33, CD45, CD117, and cMPO, weakly positive for CD34, and negative for HLA-DR and B-cell and T-cell markers. The immunofluorescence staining with the anti-PML monoclonal antibody (PG-M3) 5 was negative in both BM and peripheral blood samples. Moreover, reverse transcription polymerase chain reaction (RT-PCR) to amplify the PML/RARA fusion gene and conventional karyotyping to search for the t(15;17) were also negative. Due to the clinical suspicion of acute promyelocytic leukemia, the patient was started on all-trans retinoic ac...

show abstract

Redundant function of retinoic acid receptor isoforms in leukemogenesis unravels a prominent function of genome topology and architecture in the selection of mutagenic events in cancer

Cited by 15 publications

References 8 publications

A novel NPM1-RARG-NPM1 chimeric fusion in acute myeloid leukaemia resembling acute promyelocytic leukaemia but resistant to all-trans retinoic acid and arsenic trioxide

A novel NPM1-RARG-NPM1 chimeric fusion in acute myeloid leukaemia resembling acute promyelocytic leukaemia but resistant to all-trans retinoic acid and arsenic trioxide

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

A novel NUP98/RARG gene fusion in acute myeloid leukemia resembling acute promyelocytic leukemia

Contact Info

Product

Resources

About