Publications by authors named "Ryan Hiltenbrand"

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins.

View Article and Find Full Text PDF
Article Synopsis
  • UBTF tandem duplications (UBTF-TDs) are common alterations in both pediatric and adult acute myeloid leukemia (AML), linked to poor chemotherapy response and unique transcriptional profiles similar to other leukemia subtypes.
  • This study investigated how UBTF-TD influences leukemia, finding that it mislocalizes to specific genomic regions, affecting crucial gene clusters like HOXA/HOXB and MEIS1, which are relevant in these malignancies.
  • The research also showed that targeting UBTF-TD with the menin inhibitor SNDX-5613 effectively reduces tumor growth and alters the expression profile in leukemia cells, presenting a potential treatment option for this aggressive form of AML.
View Article and Find Full Text PDF

An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines.

View Article and Find Full Text PDF

Unlabelled: 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 (UBTF) in 9% of relapsed AML cases.

View Article and Find Full Text PDF

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 , a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to .

View Article and Find Full Text PDF

Pediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations.

View Article and Find Full Text PDF

Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n = 28, tAML: n = 56).

View Article and Find Full Text PDF

Using a time-course RNA-seq analysis we identified transcriptomic changes during formation of nodule-like structures (NLS) in rice and compared rice RNA-seq dataset with a nodule transcriptome dataset in Medicago truncatula. Plant hormones can induce the formation of nodule-like structures (NLS) in plant roots even in the absence of bacteria. These structures can be induced in roots of both legumes and non-legumes.

View Article and Find Full Text PDF

Several studies have shown that plant hormones play important roles during legume-rhizobia symbiosis. For instance, auxins induce the formation of nodule-like structures (NLSs) on legume roots in the absence of rhizobia. Furthermore, these NLS can be colonized by nitrogen-fixing bacteria, which favor nitrogen fixation compared to regular roots and subsequently increase plant yield.

View Article and Find Full Text PDF

A PHP Error was encountered

Severity: Notice

Message: fwrite(): Write of 34 bytes failed with errno=28 No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 272

Backtrace:

A PHP Error was encountered

Severity: Warning

Message: session_write_close(): Failed to write session data using user defined save handler. (session.save_path: /var/lib/php/sessions)

Filename: Unknown

Line Number: 0

Backtrace: