Myeloid Sarcoma Type of Acute Promyelocytic Leukemia With a Cryptic Insertion of RARA Into FIP1L1: The Clinical Utility of NGS and Bioinformatic Analyses

Abstract

BackgroundAcute promyelocytic leukemia (APL) is characterized by the presence of coagulopathy at onset and translocation t (15; 17) (q22; 21), meanwhile, other translocation variants of APL have also been reported. The FIP1L1–RARA fusion gene has recently been reported as a novel RARA-associated fusion gene.ObjectivesWe report a case of de novo myeloid sarcoma (MS) type of APL with FIP1L1–RARA found by next-generation sequencing (NGS) that was not detected by conventional analyze analysis for RARA translocations.MethodsWe performed typical morphological, magnetic resonance imaging (MRI), conventional tests for PML–RARA dual-fusion translocation probe, high-through sequencing and NGS. Meanwhile, bioinformatics analyses were done by using public repositories, including ONCOMINE, COSMIC, and GeneMANIA analysis.ResultsA 28-month-old girl with a complex karyotype that includes 46,XX,t(4;17)(q12;q22)[9]/46,idem,del(16)(q22)[3]/45,idem,-x,-4,-9,-15,del(16)(q22),+marl,+mar2,+mar3[7]/46,xx[3], c.38G>A (p.Gly13Asp) in the KRAS gene, and a cryptic insertion of RARA gene into the FIP1L1 gene was diagnosed with APL complicated by the de novo MS.ConclusionWe report a FIP1L1–RARA fusion in a child with APL who presented with an extramedullary tumor in the skull without the classic karyotype using NGS, whom we treated with good results. NGS analysis should be considered for APL variant cases. Further experimental studies to the association between the mutation in KRAS gene and FIP1L1–RARA fusion on the clinical phenotype and progression of APL are needed to identify more effective therapeutic targets for APL.

Acute promyelocytic leukemia with FIP1L1::RARA fusion gene: The clinical utility of transcriptome sequencing and bioinformatic analyses

“…However, FIP1L1::RARA was still positive after the second course. Then she received three cycles of ATRA and idarubicin in the following consolidation treatment and continual therapy with ATRA with chemotherapy as previously described and kept leukemia-free after a 5-month follow-up ( 11 ). During this case, the efficacy of the combination ATRA-chemotherapy therapy is positive, but the response to ATRA could not be assessed.…”

“…Besides, a FIP1L1::RARA fusion was reported in a 28-month-old girl with APL who presented with an extramedullary tumor in the skull without the classic karyotype. An initial complete remission was achieved by a treatment combining ATRA with DA regimen (daunorubicin and cytarabine) and kept leukemia-free after a 5-month follow-up by continual therapy ( 11 ).…”

Sarcoma Mieloide como apresentação de recaída precoce de Leucemia Promielocítica Aguda: uma manifestação rara – relato de caso e revisão de literatura

“…A associação com o gene de fusão FIP1L1-RARA, por exemplo, foi descrita pela primeira vez em 2008. [19] Em relação ao sítio extramedular do SM na LPA, os mais acometidos são pele e SNC. [3,6,7,13,18] Outros sítios comumente envolvidos são gengiva, pulmões, mediastino, linfonodos, testículos e mamas.…”

“…Já o ATO degrada todas as moléculas contendo PML e promove apoptose. [19] É importante ressaltar que as outras possíveis fusões gênicas de RARa podem causar resistência ao tratamento com ATO, devido à falta de sítio de ligação ao ATO (PML). Percebese que o envolvimento genético na LPA tem importância na escolha terapêutica e avaliação prognóstica.…”

“…Logo, sempre que possível, deve-se combinar a citogenética, FISH e PCR ao NGS para um diagnóstico preciso, sobretudo quando os rearranjos de RARa não são identificados pelos métodos convencionais. [19] Atualmente, na indução e consolidação, a combinação de ATRA e ATO é considerada padrão ouro em LPA de risco baixo a intermediário, com significativa redução de mielossupressão e da taxa de infecções. [2,20,26] Pacientes de alto risco geralmente requerem a associação com quimioterapia, como antraciclina ou um anticorpo droga-conjugado, como Gemtuzumabe Ozogamicina.…”