Fusion driven JMML: a novel CCDC88C–FLT3 fusion responsive to sorafenib identified by RNA sequencing

Chao, Alexander K; Meyer, Julia; Lee, Alex G.; Hecht, Anna; Tarver, Theodore C.; Ziffle, Jessica Van; Koegel, Ashley K.; Golden, Carla; Braun, Benjamin S.; Sweet-Cordero, E. Alejandro; Smith, Catherine C.; Dvorak, Christopher C.; Loh, Mignon L.; Stieglitz, Elliot

doi:10.1038/s41375-019-0549-y

Cited by 33 publications

(35 citation statements)

References 15 publications

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“…Moderately intense chemotherapy yielded a molecular remission in six of 16 (38%) versus zero of 4 (0%) for 6‐MP alone versus one of one (100%) for azacitidine alone. Patient UPN2964, who was found to have a novel fusion involving FLT3 (manuscript describing this case in press), showed a response to therapy only after the addition of the FLT3‐inhibitor sorafenib to chemotherapy.…”

Section: Resultsmentioning

confidence: 99%

Molecular assessment of pretransplant chemotherapy in the treatment of juvenile myelomonocytic leukemia

Hecht

Meyer

Chehab

et al. 2019

Pediatric Blood & Cancer

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Background: Despite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre-HCT therapy has an effect on the molecular burden of disease and how this affects outcome post-HCT.Procedure: Twenty-one patients with JMML who received pre-HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre-HCT therapy, using custom amplicon next-generation sequencing.Results: Of the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate-intensity chemotherapy, one patient received only azacitidine. The 5-year progression-free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of highintensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre-HCT therapy. Conclusions:Despite the myelodysplastic nature of JMML, patients treated with pre-HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post-HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.

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Section: Resultsmentioning

confidence: 99%

Molecular assessment of pretransplant chemotherapy in the treatment of juvenile myelomonocytic leukemia

Hecht

Meyer

Chehab

et al. 2019

Pediatric Blood & Cancer

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“…Clinical features such as age, hemoglobin F, platelet counts ( Niemeyer et al, 1997 ) and gene expression signatures ( Bresolin et al, 2010 ) were proven to have prognostic value. In recent years, development of the molecular biology toolbox has identified secondary mutations ( Caye et al, 2015 ; Stieglitz et al, 2015 ; Coppe et al, 2018 ; Murakami et al, 2018 ), novel fusion genes ( Lipka et al, 2017 ; Murakami et al, 2018 ; Chao et al, 2020 ), aberrant genomic DNA methylation ( Lipka et al, 2017 ; Stieglitz et al, 2017 ; Murakami et al, 2018 ; Chao et al, 2020 ), and dysregulation in the non-coding transcriptome (microRNA, miRNA, and long non-coding RNA, lncRNAs, Leoncini et al, 2016 ; Hofmans et al, 2018 ) as molecular mechanisms associated with JMML pathogenesis and linked to prognostic relevance.…”

Section: Introductionmentioning

confidence: 99%

CircRNAs Dysregulated in Juvenile Myelomonocytic Leukemia: CircMCTP1 Stands Out

Molin

Hofmans

Gaffo

et al. 2021

Front. Cell Dev. Biol.

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Juvenile myelomonocytic leukemia (JMML), a rare myelodysplastic/myeloproliferative neoplasm of early childhood, is characterized by clonal growth of RAS signaling addicted stem cells. JMML subtypes are defined by specific RAS pathway mutations and display distinct gene, microRNA (miRNA) and long non-coding RNA expression profiles. Here we zoom in on circular RNAs (circRNAs), molecules that, when abnormally expressed, may participate in malignant deviation of cellular processes. CirComPara software was used to annotate and quantify circRNAs in RNA-seq data of a “discovery cohort” comprising 19 JMML patients and 3 healthy donors (HD). In an independent set of 12 JMML patients and 6 HD, expression of 27 circRNAs was analyzed by qRT-PCR. CircRNA-miRNA-gene networks were reconstructed using circRNA function prediction and gene expression data. We identified 119 circRNAs dysregulated in JMML and 59 genes showing an imbalance of the circular and linear products. Our data indicated also circRNA expression differences among molecular subgroups of JMML. Validation of a set of deregulated circRNAs in an independent cohort of JMML patients confirmed the down-regulation of circOXNAD1 and circATM, and a marked up-regulation of circLYN, circAFF2, and circMCTP1. A new finding in JMML links up-regulated circMCTP1 with known tumor suppressor miRNAs. This and other predicted interactions with miRNAs connect dysregulated circRNAs to regulatory networks. In conclusion, this study provides insight into the circRNAome of JMML and paves the path to elucidate new molecular disease mechanisms putting forward circMCTP1 up-regulation as a robust example.

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“…Rarely, these children harbor germline or somatic activating RRAS mutations [ 23 , 50 ]. Recently, a CCDC88C-FLT3 fusion responsive to sorafenib was described in a pediatric patient with clinical features of JMML and monosomy 7 [ 51 ]. Other fusions detected in children with myeloproliferative disease include ALK [ 52 , 53 ], ROS1 [ 52 , 53 ], FIP1L1-RARA [ 54 ], HCMOGT-1-PDGFRB [ 55 ], NDEL1-PDGFRB [ 56 ], and NUP98-HOXA11 [ 57 ].…”

Section: The Origin Of Jmml: the Ras Pathwaymentioning

confidence: 99%

“…Although kinase fusion-positive cases without Ras pathway mutation may fulfill the clinical and diagnostic criteria of JMML, they likely represent a genetically distinct myeloproliferative neoplasm in childhood. When identified, these tyrosine kinase fusions offer an attractive target for personalized therapies [ 51 , 53 ].…”

Section: The Origin Of Jmml: the Ras Pathwaymentioning

confidence: 99%

Current Treatment of Juvenile Myelomonocytic Leukemia

Mayerhofer

Niemeyer

Flotho

2021

JCM

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Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations. NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.

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Fusion driven JMML: a novel CCDC88C–FLT3 fusion responsive to sorafenib identified by RNA sequencing

Cited by 33 publications

References 15 publications

Molecular assessment of pretransplant chemotherapy in the treatment of juvenile myelomonocytic leukemia

Molecular assessment of pretransplant chemotherapy in the treatment of juvenile myelomonocytic leukemia

CircRNAs Dysregulated in Juvenile Myelomonocytic Leukemia: CircMCTP1 Stands Out

Current Treatment of Juvenile Myelomonocytic Leukemia

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