Biology subjects

Maciejewski, J.

Publications and source records attributed to Maciejewski, J..

4 recordsLinked to original sources

bioRxiv2026

Persistent Malignant Stem Cells Drive Relapse After Transplantation in the Myelodysplastic Neoplasms

The myelodysplastic neoplasms (MDS) are initiated in hematopoietic stem cells (HSCs). Allogeneic transplantation is the only curative treatment, but relapse remains common. To detect rare MDS HSCs, we developed an ultra-low-input DNA sequencing assay and applied it to a multicenter post-transplant cohort. HSC mutation detection preceded relapse by a mean of 98 days and strongly predicted relapse (95.7% vs. 30.3%; hazard ratio, 8.8; P=1.5e-7). Mutations detected only in unfractionated marrow did not predict relapse. We developed methods to measure donor-host HSC chimerism, improving relapse prediction sensitivity. Single-cell protein, DNA, and RNA analyses with mitochondrial lineage tracing confirmed MDS cell enrichment within immunophenotypically- and transcriptionally-defined HSCs, identifying shared ribosomal gene downregulation and candidate mechanisms of venetoclax sensitivity. Venetoclax/azacytidine depleted detectable MDS HSCs in longitudinally evaluated patients. These findings establish that HSC mutation detection predicts post-transplant relapse, provide a rationale for preemptive intervention, and define shared biological features of transplant-resistant MDS HSCs.

cancer biology↗

bioRxiv2026

Combined Menin and XPO1 inhibition drive synergistic antileukemic activity in KMT2Ar and NPM1-m AML

Menin scaffolds the oncogenic histone-lysine-N-methyltransferase (KMT2A)-fusion protein (FP) complex in KMT2A-r and wild-type KMT2A complex in NPM1-m acute myeloid leukemia (AML). Menin inhibitors (MIs) are effective in KMT2A-r AML and NPM1-m AML. However, not all patients respond to MIs as monotherapy. In this preclinical study, we demonstrate that the MI ziftomenib, in combination with the XPO1 inhibitor selinexor, synergistically inhibited the growth of multiple KMT2A-r and NPM1-m AML cell lines (CI<1). The combination suppressed colony formation in primary CD34+ KMT2A-r progenitor cells without affecting normal stem cells. Robust apoptosis and decreased G2/M populations were also evident. The combination downregulated HOXA9 and MEIS1 while upregulating monocytic differentiation marker CD11b in both the AML molecular signatures. RNA sequencing and proteomic analysis in KMT2A-r revealed suppression of multiple bona fide menin-KMT2A target genes. Our mechanistic studies also identified a novel role of XPO1 in stabilizing menins binding to chromatin and its interactions with KMT2A and KMT2A/MLLT3. XPO1 inhibitor-mediated disruption of these interactions, particularly in combination with ziftomenib, synergistically impairs oncogenic transcriptional programs. In vivo, combination therapy improved survival in both MV4;11 and OCI-AML3 cell line and primary patient-derived KMT2A-r and NPM1-m AML xenograft models in NSG mice, effective even at reduced drug doses. These preclinical findings demonstrate that simultaneous inhibition of the menin-KMT2A interaction and XPO1 can be a more effective translational strategy for treating KMT2A-r and NPM1-m AML than MI monotherapy to deepen responses and delay/prevent relapses.

cancer biology↗

bioRxiv2020

Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network

Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a nucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). We report here that DNMT1 protein, although substantially depleted (~50%) in patients bone marrows at response, rebounded at relapse, and explaining this, we found pyrimidine metabolism gene expression shifts averse to the processing of each pro-drug. The same metabolic shifts observed clinically were rapidly recapitulated in leukemia cells exposed to the pro-drugs in vitro. Pyrimidine metabolism is a network that senses and preserves nucleotide balances: Decitabine, a deoxycytidine analog, and 5-azacytidine, a cytidine analog, caused acute and distinct nucleotide imbalances, by off-target inhibition of thymidylate synthase and ribonucleotide reductase respectively. Resulting expression changes in key pyrimidine metabolism enzymes peaked 72-96 hours later. Continuous pro-drug exposure stabilized metabolic shifts generated acutely, preventing DNMT1-depletion and permitting exponential leukemia out-growth as soon as day 40. Although dampening to activity of the pro-drug initially applied, adaptive metabolic responses primed for activity of the other. Hence, in xenotransplant models of chemorefractory AML, alternating decitabine with 5-azacytidine, timed to exploit compensating metabolic shifts, and addition of an inhibitor of a catabolic enzyme induced by decitabine/5-azacytidine, extended DNMT1-depletion and time-to-distress by several months versus either pro-drug alone. In sum, resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network; these responses can be anticipated and thus exploited. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/958405v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@e3f77aorg.highwire.dtl.DTLVardef@8caaa4org.highwire.dtl.DTLVardef@117236dorg.highwire.dtl.DTLVardef@16ee98_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in specific and relevant biological pathways, allowing regulators of human erythropoiesis and modifiers of blood diseases to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.

genomics↗