Characterization of a cryptic KMT2A/AFF1 gene fusion by mate-pair sequencing (MPseq) in a young adult with newly diagnosed B-lymphoblastic leukemia

Peterson, Jess F.; Smoley, Stephanie A.; Luoma, Ivy; Pitel, Beth A.; Rice, Christopher S.; Demasi, Jonna C. Benevides; Vasmatzis, George; Smadbeck, James B.; Yang, Tong; Greipp, Patricia T.; Ketterling, Rhett P.; Baughn, Linda B.

doi:10.1007/s12308-019-00355-x

Cited by 2 publications

(2 citation statements)

References 12 publications

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“…92 Acquired genetic and chromosomal aberrations result in fusion of KMT2A to over 100 different partners, 93 with most conferring a poor prognosis. 47 KMT2Ar may be cryptic, necessitating complementary molecular methods such as fluorescence in situ hybridisation, 94 NGS, 95,96 optical genome mapping 97,98 or whole-genome sequencing 21 for detection. Mutations in nucleophosmin 1 (NPM1 mut ) are present in up to 30% of ND AML 23 and 12% of RR AML, including first salvage (64%) and salvage 2 and beyond (36%).…”

Section: K Mt2a R E a R R A Nge M E N Ts A N D N Pm1 M U Tat Ionsmentioning

confidence: 99%

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease

Jen,

Kantarjian,

Kadia

et al. 2024

Br J Haematol

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SummaryThe treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation‐targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A‐rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision‐making in both intensive and low‐intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on‐label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

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Section: K Mt2a R E a R R A Nge M E N Ts A N D N Pm1 M U Tat Ionsmentioning

confidence: 99%

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease

Jen,

Kantarjian,

Kadia

et al. 2024

Br J Haematol

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“…Previously described gene fusions and SNVs represent only a portion of clinically relevant genomic alterations affecting ALL patients, limiting the applicability of RaScALL. To enable detection of a broader range of genomic alterations, we performed a literature search identifying an additional 46 gene fusions and 26 SNVs reported in multiple ALL patients and associated with functional effects [5,8,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. Targets for these variants, and any alterations undetected in the study cohort, were generated using RaScALL's custom target generation tool (see Materials and Methods), resulting in an expanded target set representing 75 distinct gene fusions and sequence variants affecting 14 cancer-related genes (S5 Table ).…”

Section: Rascall Accurately Identifies Subtype Defining Alterations I...mentioning

confidence: 99%

RaScALL: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL)

Rehn

Mayoh²,

Heatley³

et al. 2022

PLoS Genet

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RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, integrating RNA-seq in a clinical setting requires rapid detection and accurate reporting of clinically relevant alterations. Here we present RaScALL, an implementation of the k-mer based variant detection tool km, capable of identifying more than 100 prognostically significant lesions observed in ALL, including gene fusions, single nucleotide variants and focal gene deletions. We compared genomic alterations detected by RaScALL and those reported by alignment-based de novo variant detection tools in a study cohort of 180 Australian patient samples. Results were validated using 100 patient samples from a published North American cohort. RaScALL demonstrated a high degree of accuracy for reporting subtype defining genomic alterations. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% of reported cases in the study cohort (n = 164) and 95% of samples (n = 63) in the validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n = 12) and IKZF1 p.N159Y (n = 4). Intragenic IKZF1 deletions resulting in aberrant transcript isoforms were also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches. The application of RaScALL enables rapid identification and reporting of previously identified genomic alterations of known clinical relevance.

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Characterization of a cryptic KMT2A/AFF1 gene fusion by mate-pair sequencing (MPseq) in a young adult with newly diagnosed B-lymphoblastic leukemia

Cited by 2 publications

References 12 publications

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease

RaScALL: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL)

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