RNA splicing factor mutations drive myeloid neoplasm oncogenesis through protein complex poisoning
- 1Karolinska Institutet
Abstract
RNA splicing factor mutations (SFmut) are founding oncogenic events which cause RNA splicing errors with unpredictable gene expression dynamics. Despite extensive transcriptomic studies, SFmut cancer-initiating mechanisms remain elusive. Among SFmut cancers, myeloid neoplasms (MN) alone offer a setting where true cancer-driving SFmut stem cells can be identified, namely the hematopoietic stem cell (HSC). Within a cohort of 62 MN patients and 20 healthy donors, we conducted long/short-read single-cell transcriptomics (10X-ONT, n = 21) and immunophenotype-resolved low-cell proteomics (pauciproteomics, n = 78) to resolve gene expression, RNA splicing and protein expression dynamics across healthy and SFmut MN hematopoiesis. During hematopoietic differentiation, SFmut RNA mis-splicing decouples proteotranscriptomic dynamics in a mutation-specific manner. Pauciproteomics defines the functional effects of SFmut RNA mis-splicing on the protein layer, identifying early-stage protein effects which poison entire functional protein complexes and progressively disrupt the proteome-wide network during cellular maturation. Importantly, this information could neither be resolved nor predicted by transcriptomic analyses. Finally, we functionally validate the proteome dynamics of HSC through induced pluripotent stem cell culture models of early hematopoietic differentiation, identifying candidate mechanisms for SFmut oncogenesis. Overall, these data elucidate SFmut MN disease biology with unprecedented granularity, defining the molecular consequences of SFmut RNA mis-splicing and offering a generalizable framework for cancer stem cell studies.
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BibTeX
@misc{moura2026splicing,
title = {{RNA splicing factor mutations drive myeloid neoplasm oncogenesis through protein complex poisoning}},
author = {P. L. Moura and R. M. M. Branca and Y. Kaminskiy and I. Siavelis and K. R. Shrung and S. Hofmann and C. M. Perraki and A. Argyriou and S. Fazeli and M. M. Nakagawa and T. Mortera-Blanco and S. Boettcher and C. Kubaczka and T. M. Schlaeger and M. Creignou and I. Barbosa and A.-C. Björklund and M. Hillberg Widfeldt and D. Bosch and S. Massaar and M. Sanders and F. Fagerström-Billai and G. Rowe and P. S. Woll and S. E. W. Jacobsen and J. Ungerstedt and Y. Nannya and V. Lundin and S. Ogawa and J. Lehtiö and E. Hellström-Lindberg},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.754980},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.754980v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - RNA splicing factor mutations drive myeloid neoplasm oncogenesis through protein complex poisoning
AU - P. L. Moura
AU - R. M. M. Branca
AU - Y. Kaminskiy
AU - I. Siavelis
AU - K. R. Shrung
AU - S. Hofmann
AU - C. M. Perraki
AU - A. Argyriou
AU - S. Fazeli
AU - M. M. Nakagawa
AU - T. Mortera-Blanco
AU - S. Boettcher
AU - C. Kubaczka
AU - T. M. Schlaeger
AU - M. Creignou
AU - I. Barbosa
AU - A.-C. Björklund
AU - M. Hillberg Widfeldt
AU - D. Bosch
AU - S. Massaar
AU - M. Sanders
AU - F. Fagerström-Billai
AU - G. Rowe
AU - P. S. Woll
AU - S. E. W. Jacobsen
AU - J. Ungerstedt
AU - Y. Nannya
AU - V. Lundin
AU - S. Ogawa
AU - J. Lehtiö
AU - E. Hellström-Lindberg
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.754980
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.754980v1
AB - RNA splicing factor mutations (SFmut) are founding oncogenic events which cause RNA splicing errors with unpredictable gene expression dynamics. Despite extensive transcriptomic studies, SFmut cancer-initiating mechanisms remain elusive. Among SFmut cancers, myeloid neoplasms (MN) alone offer a setting where true cancer-driving SFmut stem cells can be identified, namely the hematopoietic stem cell (HSC). Within a cohort of 62 MN patients and 20 healthy donors, we conducted long/short-read single-cell transcriptomics (10X-ONT, n = 21) and immunophenotype-resolved low-cell proteomics (pauciproteomics, n = 78) to resolve gene expression, RNA splicing and protein expression dynamics across healthy and SFmut MN hematopoiesis. During hematopoietic differentiation, SFmut RNA mis-splicing decouples proteotranscriptomic dynamics in a mutation-specific manner. Pauciproteomics defines the functional effects of SFmut RNA mis-splicing on the protein layer, identifying early-stage protein effects which poison entire functional protein complexes and progressively disrupt the proteome-wide network during cellular maturation. Importantly, this information could neither be resolved nor predicted by transcriptomic analyses. Finally, we functionally validate the proteome dynamics of HSC through induced pluripotent stem cell culture models of early hematopoietic differentiation, identifying candidate mechanisms for SFmut oncogenesis. Overall, these data elucidate SFmut MN disease biology with unprecedented granularity, defining the molecular consequences of SFmut RNA mis-splicing and offering a generalizable framework for cancer stem cell studies.
ER -