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Publications

Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms


Taylor J, Mi X, North K, Binder M, Penson A, Lasho T, Knorr K, Haddadin M, Liu B, Pangallo J, Benbarche S, Wiseman D, Tefferi A, Halene S, Liang Y, Patnaik MM, Bradley RK, Abdel-Wahab O.
Blood Sep 2020
Abstract

Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring ≥2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q < .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, ∼50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.

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Area

Heme

Institution Type

Academia

Indication / Modality

Myeloproliferative Neoplasms (MPN), Myelodysplastic Syndrome (MDS), Acute Myleoid Leukemia (AML)

Goal of Study

Clinical Profiling

Key Genes

SF3B1, SRSF2, U2AF1

PAD Project

No

Analytes Assessed

InDels, SNV

Sample Storage

Frozen

Sample Prep

Whole Cells

Sample Type

Patient Material

Tissue / Organ

Bone Marrow Aspirates

Species

Human

Panel Used

Custom

Proof Point Demonstrated

Co-occurrence, Phylogeny, Clonality
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