Biology subjects

Tallman, M. S.

Publications and source records attributed to Tallman, M. S..

4 recordsLinked to original sources

bioRxiv2023

Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes

Acute myeloid leukemia (AML) is an aggressive disease with complex and heterogeneous biology. Although several genomic classifications have been proposed, there is a growing interest in going beyond genomics to stratify AML. In this study, we profile the sphingolipid family of bioactive molecules in 213 primary AML samples and 30 common human AML cell lines. Using an integrative approach, we identify two distinct sphingolipid subtypes in AML characterized by a reciprocal abundance of hexosylceramide (Hex) and sphingomyelin (SM) species. The two Hex-SM clusters organize diverse samples more robustly than known AML driver mutations and are coupled to latent transcriptional states. Using transcriptomic data, we develop a machine-learning classifier to infer the Hex-SM status of AML cases in TCGA and BeatAML clinical repositories. The analyses show that the sphingolipid subtype with deficient Hex and abundant SM is enriched for leukemic stemness transcriptional programs and comprises an unappreciated high-risk subgroup with poor clinical outcomes. Our sphingolipid-focused examination of AML identifies patients least likely to benefit from standard of care and raises the possibility that sphingolipidomic interventions could switch the subtype of AML patients who otherwise lack targetable alternatives. Key Points1.Sphingolipidomics separates acute myeloid leukemia (AML) patients and cell lines into two subtypes. 2.The subtype with low hexosylceramide and high sphingomyelin defines a new high-risk subtype with poor clinical outcomes.

systems biology↗

bioRxiv2020

Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess crosslineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without PDC expansion. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.Competing Interest StatementConflict-of-interest disclosure: W.X. has received research support from Stemline Therapeutics. S.F.C. is a consultant for Imago Biosciences and has received honoraria from DAVA Oncology. A.D.G. served on advisory boards or as a consultant for Abbvie, Aptose, Celgene, Daiichi Sanyko, Genentech, received research funding from Abbvie, ADC Therapeutics, Aprea, AROG, Daiichi Sanyko, Pfizer, received Honoraria from Dava Oncology. R.K.R has received consulting fees from: Constellation, Incyte, Celgene, Promedior, CTI, Jazz Pharmaceuticals, Blueprint, Stemline, and research funding from Incyte, Constellation, and Stemline Therapeutics. M.S.T has received research funding from AbbVie, Cellerant, Orsenix, ADC Therapeutics, Biosight, Glycomimetics, Rafael Pharmaceuticals and Amgen. He also served on advisory Boards for AbbVie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, Jazz Pharma, Roche, Biosight and Novartis. He received royalties from UpToDate. R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Loxo (until 2019), Auron, Ajax, Mission Bio, Imago, C4 Therapeutics and Isoplexis, which each include an equity interest. He receives research support from and consulted for Celgene and Roche, he has received research support from Prelude Therapeutics, and he has consulted for Incyte, Novartis and Janssen. He has received honoraria from Lilly and Amgen for invited lectures and from Gilead for grant reviews.View Full Text

pathology↗

bioRxiv2020

Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition

Previous studies have established that the cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity. However, the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to cytotoxic chemotherapy and express high levels of the transcription factor Evi1 compared to leukemias derived from myeloid progenitors. Here, we compared drug sensitivity and expression profiles of murine and human leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for Evi1 in modulating p53 protein stability and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 inhibitors in addition to classical genotoxic stresses. p53 loss-of-function in Evi1low progenitor-derived leukemias induces resistance to LSD1 inhibition. By contrast, Evi1high leukemias are sensitized to LSD1 inhibition by the BH3 mimetic venetoclax, resulting in enhanced apoptosis and greater reductions in disease burden. Our findings demonstrate a cell-of-origin determined novel role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in high-risk, chemoresistant EVI1high AML.

cancer biology↗

bioRxiv2018

Isoform switching as a mechanism of acquired resistance to isocitrate dehydrogenase inhibition

Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors.\n\nSignificanceIDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by \"isoform switching\" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2-hydroxyglutarate (2HG) production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.

cancer biology↗