Richard W. Kriwacki
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View article: Tandem duplications in UBTF create XPO1-dependent nuclear export signals that reveal a leukemic therapeutic dependency
Tandem duplications in UBTF create XPO1-dependent nuclear export signals that reveal a leukemic therapeutic dependency Open
UBTF tandem duplications (UBTF-TDs) define a high-risk molecular subtype of acute myeloid leukemia (AML). While menin inhibitors show therapeutic promise in UBTF-TD AMLs, acquired resistance remains a challenge. Here, we used proteomic, ep…
View article: TMOD-14. Synthetic ZFTA-fusions pinpoint IDR acquisition as a mechanism of brain tumor development
TMOD-14. Synthetic ZFTA-fusions pinpoint IDR acquisition as a mechanism of brain tumor development Open
Over 95% of ependymomas (EPN) that arise in the cortex are characterized by gene fusions commonly involving the zinc finger translocation associated (ZFTA) protein. These fusion oncoproteins (FOs) join ZFTA with either a transcription fact…
View article: EXTH-74. Nuclear Transport as a Therapeutic Vulnerability in ZFTA-RELA Ependymoma
EXTH-74. Nuclear Transport as a Therapeutic Vulnerability in ZFTA-RELA Ependymoma Open
Ependymoma (EPN) is the third most common pediatric brain tumor with no targeted therapies available to patients. The most frequent driver alteration is a gene fusion between ZFTA and RELA (denoted ZR), which leads to constitutive localiza…
View article: Supplementary Figure S8 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Figure S8 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Figure S8 shows that KAT6A/7 and Menin inhibition have combinatorial effects in vivo.
View article: Supplementary Figure S1 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Figure S1 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Figure S1 shows that some NUP98 fusions drive cell transformation and leukemogenesis.
View article: Supplementary Figure S7 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Figure S7 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Figure S7 shows that KAT6A/7 and Menin inhibition alter gene expression and remodel chromatin in NUP98-rearranged cells.
View article: Data from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Data from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
NUP98 fusion oncoproteins (FO) are a hallmark of childhood acute myeloid leukemia. NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell–associated genes i…
View article: Supplementary Figure S4 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Figure S4 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Figure S4 shows that MYST family histone acetyltransferase complex members are molecular dependencies in NUP98-rearranged cells.
View article: Supplementary Tables S1-S17 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Tables S1-S17 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Table S1. Exonic mutations/indels in Nup98::Kdm5a;Vav-Cre tumors developing after bone marrow transplant Supplementary Table S2. Exonic mutations/indels in spontaneous Nup98::Kdm5a;Vav-Cre tumors Supplementary Table S3. Enric…
View article: Supplementary Figure S3 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Figure S3 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Figure S3 shows that NUP98 fusion oncoproteins interact with MYST family histone acetyltransferase complex members.
View article: Supplementary Figure S5 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Figure S5 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Figure S5 shows that NUP98-rearranged cells respond to KAT6A/7 inhibition in vitro and in vivo.
View article: Supplementary Figure S2 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Figure S2 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Figure S2 shows that Nup98::Kdm5a;Vav-Cre mice spontaneously develop myeloid disease.
View article: Supplementary Figure S6 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Figure S6 from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Figure S6 shows that KAT6A/7 and Menin inhibition have synergistic effects in NUP98-rearranged cells.
View article: Supplementary Methods and Results from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia
Supplementary Methods and Results from KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
Supplementary Methods, Supplementary Results
View article: Synthetic ZFTA fusions pinpoint disordered protein domain acquisition as a mechanism of brain tumorigenesis
Synthetic ZFTA fusions pinpoint disordered protein domain acquisition as a mechanism of brain tumorigenesis Open
View article: Phase separation via protein-protein and protein-RNA networks coordinates ribosome assembly in the nucleolus
Phase separation via protein-protein and protein-RNA networks coordinates ribosome assembly in the nucleolus Open
The nucleolus, the largest membraneless organelle in the nucleus, functions as the site for ribosome biogenesis. While long known for its complex and dynamic structure, our mechanistic understanding of nucleolar organization has advanced d…
View article: Protein Dynamics at Different Timescales Unlock Access to Hidden Post-Translational Modification Sites
Protein Dynamics at Different Timescales Unlock Access to Hidden Post-Translational Modification Sites Open
Summary Post-translational modifications (PTMs) alter the proteome in response to intra- and extracellular signals, providing fundamental information processing in development, homeostasis and disease 1–5 . Here, we used proteome-wide stru…
View article: KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i> -Rearranged Acute Myeloid Leukemia
KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in <i>NUP98</i> -Rearranged Acute Myeloid Leukemia Open
NUP98 fusion oncoproteins (FO) are a hallmark of childhood acute myeloid leukemia. NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell–associated genes i…
View article: TERT c.3150 G > C (p.K1050N): a founder Ashkenazi Jewish variant associated with telomere biology disorders
TERT c.3150 G > C (p.K1050N): a founder Ashkenazi Jewish variant associated with telomere biology disorders Open
View article: Proteome-wide computational analyses reveal links between protein condensate formation and RNA biology
Proteome-wide computational analyses reveal links between protein condensate formation and RNA biology Open
Biomolecular condensates mediate dynamic compartmentalization of cellular processes. The multivalent interactions that underlie biomolecular condensation are often promoted by intrinsically disordered regions (IDRs) within proteins. While …
View article: Granular component sub-phases direct ribosome biogenesis in the nucleolus
Granular component sub-phases direct ribosome biogenesis in the nucleolus Open
The hierarchical, multiphase organization of the nucleolus underlies ribosome biogenesis. Ribonucleoprotein particles that regulate ribosomal subunit assembly are heterogeneously disposed in the granular component (GC) of the nucleolus. Ho…
View article: A gated hydrophobic funnel within BAX binds long-chain alkenals to potentiate pro-apoptotic function
A gated hydrophobic funnel within BAX binds long-chain alkenals to potentiate pro-apoptotic function Open
Mitochondria maintain a biochemical environment that cooperates with BH3–only proteins (e.g., BIM) to potentiate BAX activation, the key event to initiate physiological and pharmacological forms of apoptosis. The sphingosine-1-phosphate me…
View article: MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in<i>NUP98</i>-Rearranged Acute Myeloid Leukemia
MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in<i>NUP98</i>-Rearranged Acute Myeloid Leukemia Open
NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML) and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NU…
View article: p14ARF forms meso-scale assemblies upon phase separation with NPM1
p14ARF forms meso-scale assemblies upon phase separation with NPM1 Open
View article: Disruption of cotranscriptional splicing suggests RBM39 is a therapeutic target in acute lymphoblastic leukemia
Disruption of cotranscriptional splicing suggests RBM39 is a therapeutic target in acute lymphoblastic leukemia Open
There are only a few options for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), thus, this is a major area of unmet medical need. In this study, we reveal that the inclusion of a poison exon in RBM39, which …
View article: Assembly of mTORC3 Involves Binding of ETV7 to Two Separate Sequences in the mTOR Kinase Domain
Assembly of mTORC3 Involves Binding of ETV7 to Two Separate Sequences in the mTOR Kinase Domain Open
mTOR plays a crucial role in cell growth by controlling ribosome biogenesis, metabolism, autophagy, mRNA translation, and cytoskeleton organization. It is a serine/threonine kinase that is part of two distinct extensively described protein…
View article: The genomic basis of childhood T-lineage acute lymphoblastic leukaemia
The genomic basis of childhood T-lineage acute lymphoblastic leukaemia Open
View article: EPEN-04. OVERWHELMING ZFTA-RELA NUCLEAR LOCALIZATION AS A THERAPEUTIC STRATEGY AGAINST EPENDYMOMA
EPEN-04. OVERWHELMING ZFTA-RELA NUCLEAR LOCALIZATION AS A THERAPEUTIC STRATEGY AGAINST EPENDYMOMA Open
BACKGROUND Pediatric ependymoma is a malignant brain tumor without targeted therapies. The 10-year survival is close to 50%, as this relentless tumor often relapses years following initial diagnosis. Over two thirds of supratentorial epend…
View article: EPEN-22. ZFTA FUSION ONCOPROTEINS DRIVE ONCOGENESIS THROUGH ASSEMBLY OF BIOMOLECULAR CONDENSATES
EPEN-22. ZFTA FUSION ONCOPROTEINS DRIVE ONCOGENESIS THROUGH ASSEMBLY OF BIOMOLECULAR CONDENSATES Open
BACKGROUND Ependymomas continue to be an aggressive brain tumor entity without targeted therapies. The highly recurrent fusion oncoprotein (FO), ZFTA-RELA, is known to be associated with about 70% of supratentorial ependymomas. While recen…
View article: ZFTA fusion oncoproteins drive tumorigenesis through transcriptional condensates
ZFTA fusion oncoproteins drive tumorigenesis through transcriptional condensates Open
Over 95% of EPNs that arise in the cortex are driven by a gene fusion involving the zinc finger translocation associated (ZFTA) protein. Using super-resolution and lattice light sheet microscopy, we demonstrate that the most frequent fusio…