Ulrich G. Steidl
<h6>Molecular Mechanisms and Targeting of Pre-Leukemic Stem Cells in Normal and Malignant Hematopoiesis</h6>
<p>Hematopoiesis maintains a life-long supply of the entire spectrum of highly specialized blood cells. This process relies on a small number of pluripotent hematopoietic stem cells (HSC).</p>
<p>Recent experimental evidence has shown that acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) arise from an unexepctedly diverse pool of pre-leukemic stem cells (preL-SC), preceding the formation of fully transformed leukemia stem cells (LSC). Polyclonal Pre-LSC as well as LSC are also key drivers of therapy resistance and disease progression. Defining the molecular mechanisms in pre-LSC and their progression to fully transformed LSC is critical to understanding the genesis of leukemia and to developing therapeutic strategies by which these processes can be targeted.</p>
<p>Recent findings from our own group and others have demonstrated a critical role of transcription dynamics and plasticity, as well as mediators of aberrant signaling in the genesis and function of HSC, pre-LSC and LSC. To identify and functionally study implicated pathways we are studying murine genetic models as well as primary human samples from patients with MDS and leukemia. Our studies aim at the development of targeted, pre-LSC- and LSC-directed therapies, which could ultimately also be employed for precision prevention of relapse/progression, or "cancer interception".</p>
<p>Dr. Steidl studies the molecular and cellular mechanisms that lead to two related blood diseases, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). His NIH-funded basic and translational research seeks to define the characteristics of pre-leukemic stem cells (pre-LSC), understand their progression to leukemic stems cells, and develop drug strategies to target the process. Dr. Steidl is co-director of the Albert Einstein Cancer Center's Blood Cancer Institute.</p>
<p>He was among the first researchers to demonstrate that MDS, a common precursor of AML, arises from defective blood-forming stem cells. As a result of his work, several experimental drugs targeting abnormal stem cells in patients with MDS and AML are in clinical trials.</p>
<p>In 2021, Dr. Steidl received a prestigious Outstanding Investigator Award from the National Cancer Institute (NCI) and a seven-year, $7 million grant for his research. He is author of more than 150 research papers, and has published studies in <em>Nature</em>, <em>Nature Medicine</em>, <em>Cancer Cell</em>, <em>Nature Immunology</em>, <em>Nature Chemical Biology</em>, <em>Science Translational Medicine</em>, and many others.</p>
<p><span style="text-decoration: underline;">Selected recent publications (from a total of <strong>176)</strong>:</span></p>
<p><span class="docsum-authors full-authors">Taylor SJ, Stauber J, Bohorquez O, Tatsumi G, Kumari R, Chakraborty J, Bartholdy BA, Schwenger E, Sundaravel S, Farahat AA, Wheat JC, Goldfinger M, Verma A, Kumar A, Boykin DW, Stengel KR, Poon GMK, Steidl U.<br />Genomic binding site restriction redirects pioneer transcription factor activity.<br /><strong>Nat Genet</strong>. 2024 Sept 18; doi.org/10.1038/s41588-024-01911-7</span></p>
<p><span class="docsum-authors full-authors">Gao X*, Carpenter RS*, Boulais PE*, Zhang D, Marlein CR, Li H, Smith M, Chung DJ, Maryanovich M, Will B<sup>#</sup>, Steidl U<sup>#</sup>, Frenette PS<sup>#</sup>.<br />Regulation of the hematopoietic stem cell pool by C-Kit-associated trogocytosis.<br /><strong>Science</strong>. 2024 Aug 9; 385(6709):eadp2065.</span></p>
<p><span class="docsum-authors full-authors">Terrell JR, Taylor SJ, Schneider AL, Lu Y, Vernon TN, Xhani S, Gumpper RH, Luo M, Wilson WD, Steidl U<sup>#</sup>, Poon GMK<sup>#</sup>. <br />DNA selection by the master transcription factor PU.1.<br /><strong>Cell Rep</strong>. 2023; 42(7):112671.</span></p>
<p><span class="docsum-authors full-authors">Piszczatowski RT*, Schwenger E*, Sundaravel S, Stein CM, Liu Y, Stanley P, Verma A, Zheng D, Seidel RD, Almo SC, Townley RA<sup>#</sup>, Bülow HE<sup>#</sup>, Steidl U<sup>#</sup>.<br /></span> A glycan-based approach to cell characterization and isolation: Hematopoiesis as a paradigm.<br /><span class="docsum-journal-citation full-journal-citation"><strong>J Exp Med</strong>. 2022; 219(11):e20212552.<br /></span></p>
<p><span class="docsum-authors full-authors">Ueda K, Kumari R, Schwenger E, Wheat JC, Bohorquez O, Narayanagari SR, Taylor SJ, Carvajal LA, Pradhan K, Bartholdy B, Todorova TI, Goto H, Sun D, Chen J, Shan J, Song Y, Montagna C, Xiong S, Lozano G, Pellagatti A, Boultwood J, Verma A, Steidl U.<br />MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.<br /><strong>Cancer Cell</strong>. 2021; 39:529-547<br /></span></p>
<p>Wheat JC, Sella Y, Willcockson M, Skoultchi AI, Bergman A, Singer RH, Steidl U.<br />Single Molecule Imaging of Transcription Dynamics in Somatic Stem Cells.<br /><strong>Nature</strong>. 2020; 583:431-436</p>
<p>Chen J, Kao YR, Sun D, Todorova TI, Reynolds D, Narayanagari SR, Montagna C, Will B, Verma A*, Steidl U*.<br />Myelodysplastic Syndrome Progression to Acute Myeloid Leukemia at the Stem Cell Level.<br /><strong>Nat Med</strong>. 2019; 25:103-110</p>
<p>Mitchell K, Barreyro L, Todorova TI, Taylor SJ, Antony Debré I, Narayanagari SR, Carvajal LA, Leite J, Piperdi Z, Pendurti G, Mantzaris I, Paietta E, Verma A, Gritsman K, Steidl U.<br />IL1RAP Potentiates Multiple Oncogenic Signaling Pathways in AML.<br /><strong>J Exp Med</strong>. 2018; 215:1709-1727</p>
<p>Carvajal LA, Ben-Neriah D, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T, Narayanagari SR, Wheat JC, Todorova TI, Mitchell KM, Kenworthy C, Guerlavais V, Annis DA, Bartholdy B, Will B, Anampa JD, Mantzaris I, Aivado M, Singer RH, Coleman RA, Verma A, Steidl U.<br />Dual inhibition of MDMX and MDM2 as a Therapeutic Strategy in Leukemia.<br /><strong>Science Transl Med</strong>. 2018 Apr 11; 10:eaao3003</p>
<p>Antony-Debré I, Paul A, Leite J, Mitchell K, Kim HM, Carvajal LA, Tidorova TI, Huang K, Kumar A, Farahat AA, Bartholdy B, Narayanagari SR, Chen J, Ambesi-Impiombato A, Ferrando AA, Mantzaris I, Gavathiotis E, Verma A, Will B, Boykin DW, Wilson WD, Poon GMK, Steidl U. <br />Pharmacological Inhibition of the Transcription Factor PU.1 in Leukemia. <br /><strong>J Clin Invest</strong>. 2017; 127:4297-4313</p>
<p>Stanley RF*, Piszczatowski RT*, Bartholdy B, Mitchell K, McKimpson WM, Narayanagari SR, Walter D, Todorova TI, Hirsch C, Makishima H, Will B, McMahon C, Gritsman K, Maciejewski JP, Kitsis RN, Steidl U. <br />A Myeloid Tumor Suppressor Role for NOL3. <strong><em><br /></em>J Exp Med</strong>. 2017; 214:753-771</p>
<p>Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR, Rominger C, Quinn C, Smallwood A, Wiggall KJ, Reif AJ, Schmidt SJ, Qi H, Zhao H, Joberty G, Faelth-Savitski M, Bantscheff M, Drewes G, Duraiswami C, Brady P, Groy A, Narayanagari SR, Antony-Debre I, Mitchell K, Wang HR, Kao YR, Christopeit M, Carvajal L, Barreyro L, Paietta E, Makishima H, Will B, Concha N, Adams ND, Schwartz B, McCabe MT, Maciejewski J, Verma A, Steidl U.<br />New IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia.<br /><strong>Nat Chem Biol</strong>. 2015; 11:878-886</p>
<p>Will B*, Vogler TO*, Narayanagari S, Bartholdy B, Todorova TI, da Silva Ferreira M, Chen J, Yu Y, Mayer J, Barreyro L, Carvajal L, Ben Neriah D, Roth M, van Oers J, Schaetzlein S, McMahon C, Edelmann W, Verma A, Steidl U. <br />Minimal PU.1 Reduction Induces a Preleukemic State and Promotes Development of Acute Myeloid Leukemia.<br /><strong>Nat Med</strong>. 2015; 21:1172-1181</p>
<p>Pandolfi A*, Stanley RF*, Yu Y, Bartholdy B, Pendurti G, Gritsman K, Boultwood J, Chernoff J, Verma A, Steidl U.<br />PAK1 is a Therapeutic Target in Acute Myeloid Leukemia and Myelodysplastic Syndrome.<br /><strong>Blood</strong>. 2015; 126:1118-27</p>
<p>Bartholdy B*, Christopeit M*, Will B, Mo Y, Barreyro L, Yu Y, Bhagat TD, Okoye-Okafor UC, Todorova TI, Greally JM, Levine RL, Melnick A, Verma A<sup>#</sup>, Steidl U<sup>#</sup>.<br />A human hematopoietic stem cell-commitment related DNA cytosine methylation signature is prognostic for overall survival in acute myeloid leukemia. <br /><strong>J Clin Invest</strong>. 2014; 124:1158-1167</p>
<p>Will B, Vogler TO, Bartholdy B, Garrett-Bakelman F, Mayer J, Barreyro L, Pandolfi A, Todorova TI, Okoye-Okafor UC, Stanley RF, Bhagat TD, Verma A, Figueroa ME, Melnick A, Roth M, Steidl U.<br />Special AT-rich Sequence-Binding Protein 1 (Satb1) regulates hematopoietic stem cell self-renewal by promoting quiescence and repressing differentiation commitment. <strong><br />Nat Immunol</strong>. 2013; 14:437-45</p>
<p>Kawahara M*, Pandolfi A*, Bartholdy B*, Barreyro L, Will B, Roth M, Okoye-Okafor UC, Todorova TI, Figueroa ME, Melnick A, Mitsiades CS, Steidl U.<br />H2.0-like Homeobox (HLX) Regulates Early Hematopoiesis and Promotes Acute Myeloid Leukemia.<br /><strong>Cancer Cell</strong>. 2012; 22:194–208</p>
<p>Will B, Zhou L, Vogler TO, Ben-Neriah S, Schinke C, Tamari R, Yu Y, Bhagat T, Bhattacharya S, Barreyro L, Heuck C, Mo Y, Parekh S, McMahon C, Pellagatti A, Boultwood J, Montagna C, Silverman L, Maciejewski J, Greally J, Ye BH, List A, Steidl C, Steidl U*, Verma A*.<br />Stem and progenitor cells in myelodysplastic syndromes show aberrant stage specific expansion and harbor genetic and epigenetic alterations.<br /><strong>Blood</strong>. 2012; 120:2076-2086</p>
<p>Barreyro L, Will B, Bartholdy B, Zhou L, Todorova TI, Stanley RF, Ben-Neriah S, Montagna C, Parekh S, Pellagatti A, Boultwood J, Paietta E, Ketterling RP, Cripe L, Fernandez HF, Greenberg PL, Tallman MS, Steidl C, Mitsiades CS, Verma A, Steidl U. <br />Overexpression of interleukin 1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. <br /><strong>Blood</strong>. 2012; 120:1290-1298</p>
<p>Roth M, Will B, Simkin G, Rao S, Barreyro L, Bartholdy B, Tamari R, Mitsiades CS, Verma A, Steidl U. <br />Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation.<br /><strong>Blood</strong>. 2012; 120:386-394</p>
<p>Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U.<br />Effect of the nonpeptide thrombopoetin receptor agnoist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome.<br /><strong>Blood</strong>. 2009; 114:3899-3908</p>
<p><strong><br />Review Articles and Commentaries:</strong></p>
<p><span class="docsum-authors full-authors">Taylor SJ, Steidl U. <br />Chemical restriction of PU.1 genomic binding sites activates alternate gene networks.<br /><strong>Nat Genet</strong>. 2024; doi.org/10.1038/s41588-024-01912-6</span></p>
<p><span class="docsum-authors full-authors">Piszczatowski RT, Buelow HE, Steidl U.<br />Heparan sulfates and heparan sulfate proteoglycans in hematopoiesis.<br /><strong>Blood</strong>. 2024; 143:2571-2587</span></p>
<p><span class="docsum-authors full-authors">Wheat JC, Steidl U.<br />Posttranscriptional Arid3a Deregulation in AMKL.<br /><strong>Blood</strong>. 2022; 139:637-638</span></p>
<p><span class="docsum-authors full-authors">Tatsumi G, Steidl U.<strong><br /></strong></span><span class="docsum-journal-citation full-journal-citation">Transcriptional circuit dynamics in HSPC. <br /><strong>Blood</strong>. 2021; 138:1382-1384</span></p>
<p><span class="docsum-authors full-authors">Taylor SJ, Sundaravel S, Steidl U.<br />Exploting a key transcriptional dependency: ZMYND8 and IRF8 in AML.<br /><strong>Mol Cell</strong>. 2021; 81:3445-3446</span></p>
<p><span class="docsum-authors full-authors">Wheat JC, Steidl U.<br />Gene expression at a single molecule level: Implications for MDS and AML.<br /><strong>Blood</strong>. 2021; 138:625-636</span></p>
<p><span class="docsum-authors full-authors">Ueda K, Steidl U.<br />Epigenetic Achilles' heel of AML.<br /><strong>Nature Cancer</strong>. 2021; 2:481-483<br /><br />Schwenger E, Steidl U.<br />An evolutionary approach to clonally complex hematologic disorders.<br /></span><span class="docsum-journal-citation full-journal-citation"><strong>Blood Cancer Discov</strong>. 2021 May;2(3):201-215.</span></p>
<p><span class="labs-docsum-authors full-authors">Sundaravel S, Steidl U.<br />Stem cell origins of JMML.<br /><strong>J Exp Med</strong>. 2021; 218:e20202152<br /></span></p>
<p><span class="labs-docsum-authors full-authors">Stauber J, Greally JM, Steidl U.<br />Preleukemic and leukemic evolution at the stem cell level.<br /><strong>Blood</strong>. 2021; 137:1013-1018</span></p>
<p><span class="labs-docsum-authors full-authors">Ueda K, Kumari R, Steidl U.</span> <br /><span class="labs-docsum-journal-citation full-journal-citation">Fueling clonal dominance through TRAFficking of NF-kB signaling.<br /><strong>Nat Immunol</strong>. 2020; 21:489-490</span></p>
<p>Mitchell K, Steidl U.<br />Targeting Immunophenotypic Markers on Leukemic Stem Cells: How Lessons from Current Approaches and Advances in the Leukemia Stem Cell (LSC) Model Can Inform Better Strategies for Treating Acute Myeloid Leukemia (AML).<br /><strong>Cold Spring Harb Perspect Med</strong>. 2020; 10:a036251</p>
<p>Piszczatowski RT, Steidl U.<br />Aurora Kinase A Inhibition: A Mega-Hit for Myelofibrosis Therapy?<br /><strong>Clin Cancer Res</strong>. 2019; 25:4868-4870</p>
<p>Chen J, Steidl U.<br />Inhibition of HIF1α Signaling: A Grand Slam for MDS Therapy ?<br /><strong>Cancer Discovery</strong>. 2018; 8:1355-1357</p>
<p>Wheat JC, Steidl U.<br />Linking histone methylation, transcription rates, and stem cell robustness.<br /><strong>Haematologica</strong>. 2018; 103:1093</p>
<p>Taylor SJ, Steidl U. <br />Metabolic strugGLS after FLT3 inhibition in AML.<br /><strong>Blood</strong>. 2018; 131:1631-1632</p>
<p>Wheat JC, Steidl U. <br />ETO2-GLIS2: A chimeric transcription factor drives leukemogenesis through a neomorphic transcription network.<em><br /></em><strong>Cancer Cell</strong>. 2017; 31:307-308</p>
<p>Shastri A, Will B, Steidl U*, Verma A*. Stem and Progenitor Cell Alterations in Myelodysplastic Syndromes.<br /><strong>Blood</strong>. 2017; 129:1586-1594</p>
<p>Carvajal L, Steidl U. Eliminating cancer stem cells in CML with combination transcriptional therapy.<br /><strong>Cell Stem Cell</strong>. 2016; 19:6-8 </p>
<p>Stanley RF, Steidl U. Molecular mechanism of mutant CALR-mediated transformation.<br /><strong>Cancer Discovery</strong>. 2016; 6:344-346</p>
<p>Stanley RF, Steidl U. Ectopic Dnmt3b Expression Delays Leukemogenesis.<br /><strong>Blood</strong>. 2016; 127:1525-6</p>
<p>Antony-Debre I, Steidl U.<br />Functionally relevant RNA helicase mutations in familial and sporadic myeloid malignancies.<br /><strong>Cancer Cell</strong>. 2015; 27:609-611</p>
<p>Verma A, Steidl U.<br />A synthetic lethal approach targeting mutant isocitrate dehydrogenase in acute myeloid leukemia.<br /><strong>Nat Med</strong>. 2015;21:113-114</p>
<p>Will B, Steidl U.<br />Combinatorial haplo-deficient tumor suppression in 7q-deficient myelodysplastic syndrome and acute myeloid leukemia.<br /><strong>Cancer Cell</strong>. 2014; 25:555-557</p>
<p>Will B, Steidl U.<br />Stem cell fate regulation by dynein motor protein Lis1.<em><br /></em><strong>Nat Genet</strong>. 2014; 46:217-218</p>
<p>Antony-Debre I, Steidl U.<br />CDK6, a new target in MLL-driven leukemia.<br /><strong>Blood</strong>. 2014; 124:5-6</p>
<p>Elias HK, Schinke C, Bhattacharyya S, Will B, Verma A, Steidl U.<br />Stem cell origin of myelodysplastic syndromes.<br /><strong>Oncogene</strong>. 2013 Dec 16. doi: 10.1038/onc.2013.520</p>
<p>Pandolfi A, Barreyro L, Steidl U.<br />Pre-leukemic stem cells: molecular biology and clinical implications of the precursors to leukemia stem cells.<br /><strong>Stem Cells Transl Med</strong>. 2013; 2:143–150</p>