Biology subjects

Hamblin, A.

Publications and source records attributed to Hamblin, A..

5 recordsLinked to original sources

bioRxiv2026

Sequential acquisition of 1p31.1-p12 LOH and 1q Gain is a common double-hit event in relapsed/refractory myeloma

Therapy-driven genomic changes in multiple myeloma (MM) remain poorly defined. We analyzed whole-genome sequencing (WGS) data from relapsed/refractory MM (rrMM, N=386) and identified regional 1p31.1-p12 (hereafter 1pCEN, a region proximal to the centromere) loss-of-heterozygosity (LOH) as the only enriched aberration showing strong therapy-associated clonal selection (clonal timing rank fold-change = 3.7, P<2.2x10-16). This event showed enriched co-occurrence with 1qGain (OR = 2.3 (1.5-3.8), P=2x10-4) forming a recurrent "double-hit" in rrMM. To validate the clonal selection process, we examined three longitudinal cohorts (180 patients, 390 samples) and confirmed clonal expansion of 1pCEN and consistent prevalence of the 1pCEN+1q double-hit (20-24%). Survival analyses demonstrated significantly reduced progression-free survival in rrMM patients with this double-hit compared with those without. Comparison with a large newly diagnosed MM (ndMM) cohort confirmed previously-described 1p32 LOH is the prognostic locus at baseline, whereas 1pCEN is therapy-selected and largely independent of the 1p32 locus. Thus, 1pCEN+1q represents a recurrent double-hit event that clonally emerges in rrMM, conferring selective advantage under drug exposure and is distinct from the ndMM high-risk markers defined by current consensus guidelines. These findings nominate 1pCEN as a new genomic biomarker in rrMM and 1pCEN+1q may help patient stratification for therapeutic monitoring. Key PointsA therapy-driven common genomic double-hit (1p31.1-p12 LOH with 1q gain) clonally emerges in relapsed/refractory myeloma.

cancer biology↗

bioRxiv2023

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in [~]25% of patients ( chr21amp). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A, a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo, and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

cancer biology↗

bioRxiv2022

Deciphering TP53 mutant Cancer Evolution with Single-Cell Multi-Omics

TP53 is the most commonly mutated gene in human cancer, typically occurring in association with complex cytogenetics and dismal outcomes. Understanding the genetic and non-genetic determinants of TP53-mutation driven clonal evolution and subsequent transformation is a crucial step towards the design of rational therapeutic strategies. Here, we carry out allelic resolution single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukaemia (AML), a tractable model of TP53-mutant cancer evolution. All patients showed dominant TP53 multi-hit HSPC clones at transformation, with a leukaemia stem cell transcriptional signature strongly predictive of adverse outcome in independent cohorts, across both TP53-mutant and wild-type AML. Through analysis of serial samples and antecedent TP53-heterozygous clones, we demonstrate a hitherto unrecognised effect of chronic inflammation, which supressed TP53 wild-type HSPC whilst enhancing the fitness advantage of TP53 mutant cells. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukaemia, and are of broader relevance to other cancer types.

cancer biology↗

bioRxiv2019

Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia

Juvenile Myelomonocytic Leukemia (JMML) is a poor prognosis childhood leukemia usually caused by germline or somatic RAS-activating mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA-sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment with RAS-activating mutations as a \"first hit\", (2) mutations are acquired with both linear and branching patterns of clonal evolution and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal inter-patient heterogeneity of JMML-LSCs which are present in, but not confined to, the phenotypic HSC compartment. RNA-sequencing of JMML-LSCs reveals upregulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, CD96) paving the way for LSC-directed disease monitoring and therapy in this disease.

cancer biology↗

bioRxiv2018

Unraveling intratumoral heterogeneity through high-sensitivity single-cell mutational analysis and parallel RNA-sequencing

Single-cell RNA-sequencing has emerged as a powerful tool to resolve transcriptional heterogeneity. However, its application to study cancerous tissues is currently hampered by the lack of coverage across key mutation hotspots in the vast majority of cells, which prevents correlation of genetic and transcriptional readouts from the same single cell. To overcome this, we developed TARGET-seq, a method for the high-sensitivity detection of multiple mutations within single-cells from both genomic and coding DNA, in parallel with unbiased, high-depth whole transcriptome analysis. We demonstrate how this technique uniquely resolves transcriptional and genetic tumor heterogeneity in myeloproliferative neoplasm stem/progenitor cells, providing insights into deregulated pathways of mutant and non-mutant cells. TARGET-seq provides a powerful tool to resolve molecular signatures of genetically distinct subclones of tumor cells.

genomics↗