ORCID Profile
0000-0002-3319-2403
Current Organisation
St. Jude Children's Research Hospital
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Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549635.V1
Abstract: Abstract NUP98 fusion oncoproteins (FO) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid–liquid phase separation (LLPS) i in vitro /i . A predominant class of NUP98 FOs, including NUP98–HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form and how they drive leukemogenesis. Here we studied NHA9 condensates and show that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three additional leukemia-associated NUP98 FOs (NUP98–PRRX1, NUP98–KDM5A, and NUP98–LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs. Significance: We show that homotypic and heterotypic mechanisms of LLPS control NUP98–HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structures. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis. i This article is highlighted in the In This Issue feature, p. 873 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541408.V1
Abstract: Supplementary Table from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541408
Abstract: Supplementary Table from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541429
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 13-12-2021
DOI: 10.1158/2159-8290.CD-21-0674
Abstract: We show that homotypic and heterotypic mechanisms of LLPS control NUP98–HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structures. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis. This article is highlighted in the In This Issue feature, p. 873
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.C.6550658.V1
Abstract: Abstract The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor ( i UBTF /i ) in 9% of relapsed AML cases. i UBTF /i -TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring i WT1 /i mutations or i FLT3 /i -ITD but not other known oncogenic fusions. These i UBTF /i -TD events are stable during disease progression and are present in the founding clone. In addition, we observed that i UBTF /i -TD AMLs account for approximately 4% of all i de novo /i pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to i UBTF /i -TD AMLs. Collectively, these clinical, genomic, and functional data establish i UBTF /i -TD as a new recurrent mutation in AML. Significance: We defined the spectrum of mutations in relapsed pediatric AML and identified i UBTF /i -TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, i FLT3 /i -ITD and i WT1 /i alterations, and are associated with poor outcomes. i a href="loodcancerdiscov/article/doi/10.1158/2643-3230.BCD-22-0004" target="_blank" See related commentary by Hasserjian and Nardi, p. 173 /a . /i i a href="loodcancerdiscov/article/doi/10.1158/2643-3230.BCD-3-3-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 171 /a . /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541423
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22544489
Abstract: Supplementary Data from Integrated Genomic Analysis Identifies i UBTF /i Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541420
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 17-02-2022
DOI: 10.1158/2643-3230.BCD-21-0160
Abstract: We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes. See related commentary by Hasserjian and Nardi, p. 173. This article is highlighted in the In This Issue feature, p. 171.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.C.6549439
Abstract: Abstract Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of i BCL11B /i , a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose i BCL11B /i to superenhancers active in hematopoietic progenitors, or focal lifications that generate a superenhancer from a noncoding element distal to i BCL11B /i . Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed i BCL11B /i allele and association of i BCL11B /i with activated hematopoietic progenitor cell i cis /i -regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic i BCL11B /i expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. Significance: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of i BCL11B /i driven by erse structural alterations, including i de novo /i superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. i This article is highlighted in the In This Issue feature, p. 2659 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541426
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22544486
Abstract: Supplementary Data from Integrated Genomic Analysis Identifies i UBTF /i Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549635
Abstract: Abstract NUP98 fusion oncoproteins (FO) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid–liquid phase separation (LLPS) i in vitro /i . A predominant class of NUP98 FOs, including NUP98–HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form and how they drive leukemogenesis. Here we studied NHA9 condensates and show that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three additional leukemia-associated NUP98 FOs (NUP98–PRRX1, NUP98–KDM5A, and NUP98–LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs. Significance: We show that homotypic and heterotypic mechanisms of LLPS control NUP98–HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structures. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis. i This article is highlighted in the In This Issue feature, p. 873 /i /
Publisher: Spandidos Publications
Date: 19-02-2013
DOI: 10.3892/OR.2013.2293
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541414.V1
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540642.V1
Abstract: This file contains Supplementary Tables 1-15 detailing clinical and genomic information about each patient analyzed in this study, along with the results of RNA-seq and gene set enrichment analyses.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541429.V1
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541423.V1
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22544486.V1
Abstract: Supplementary Data from Integrated Genomic Analysis Identifies i UBTF /i Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541417
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: Spandidos Publications
Date: 03-06-2014
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.C.6549439.V1
Abstract: Abstract Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of i BCL11B /i , a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose i BCL11B /i to superenhancers active in hematopoietic progenitors, or focal lifications that generate a superenhancer from a noncoding element distal to i BCL11B /i . Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed i BCL11B /i allele and association of i BCL11B /i with activated hematopoietic progenitor cell i cis /i -regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic i BCL11B /i expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. Significance: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of i BCL11B /i driven by erse structural alterations, including i de novo /i superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. i This article is highlighted in the In This Issue feature, p. 2659 /i /
Publisher: Spandidos Publications
Date: 11-05-2016
DOI: 10.3892/OL.2016.4554
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.C.6550658
Abstract: Abstract The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor ( i UBTF /i ) in 9% of relapsed AML cases. i UBTF /i -TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring i WT1 /i mutations or i FLT3 /i -ITD but not other known oncogenic fusions. These i UBTF /i -TD events are stable during disease progression and are present in the founding clone. In addition, we observed that i UBTF /i -TD AMLs account for approximately 4% of all i de novo /i pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to i UBTF /i -TD AMLs. Collectively, these clinical, genomic, and functional data establish i UBTF /i -TD as a new recurrent mutation in AML. Significance: We defined the spectrum of mutations in relapsed pediatric AML and identified i UBTF /i -TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, i FLT3 /i -ITD and i WT1 /i alterations, and are associated with poor outcomes. i a href="loodcancerdiscov/article/doi/10.1158/2643-3230.BCD-22-0004" target="_blank" See related commentary by Hasserjian and Nardi, p. 173 /a . /i i a href="loodcancerdiscov/article/doi/10.1158/2643-3230.BCD-3-3-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 171 /a . /i /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540642
Abstract: This file contains Supplementary Tables 1-15 detailing clinical and genomic information about each patient analyzed in this study, along with the results of RNA-seq and gene set enrichment analyses.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541411
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540645
Abstract: This file contains Supplementary Figures 1-23 with corresponding supplementary figure legends, as well as the legends for Supplementary Tables 1-15.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541417.V1
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541411.V1
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541414
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22544483
Abstract: Supplementary Figure from Integrated Genomic Analysis Identifies i UBTF /i Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia
Publisher: Spandidos Publications
Date: 07-2013
DOI: 10.3892/OL.2013.1434
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541426.V1
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Publisher: Ivyspring International Publisher
Date: 2016
DOI: 10.7150/JCA.14713
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540645.V1
Abstract: This file contains Supplementary Figures 1-23 with corresponding supplementary figure legends, as well as the legends for Supplementary Tables 1-15.
Publisher: American Association for Cancer Research (AACR)
Date: 08-06-2021
DOI: 10.1158/2159-8290.CD-21-0145
Abstract: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by erse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. This article is highlighted in the In This Issue feature, p. 2659
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22544483.V1
Abstract: Supplementary Figure from Integrated Genomic Analysis Identifies i UBTF /i Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22544489.V1
Abstract: Supplementary Data from Integrated Genomic Analysis Identifies i UBTF /i Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541420.V1
Abstract: Supplementary Data from Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation
Location: United States of America
Location: United States of America
No related grants have been discovered for Sherif Abdelhamed.