Molecular Mechanisms and Targeting of Pre-Leukemic Stem Cells in Normal and Malignant Hematopoiesis

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).

            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.

            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".

Selected recent publications (from a total of 176):

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.
Genomic binding site restriction redirects pioneer transcription factor activity.
Nat Genet. 2024 Sept 18; doi.org/10.1038/s41588-024-01911-7

Gao X*, Carpenter RS*, Boulais PE*, Zhang D, Marlein CR, Li H, Smith M, Chung DJ, Maryanovich M, Will B^#, Steidl U^#, Frenette PS^#.
Regulation of the hematopoietic stem cell pool by C-Kit-associated trogocytosis.
Science. 2024 Aug 9; 385(6709):eadp2065.

Terrell JR, Taylor SJ, Schneider AL, Lu Y, Vernon TN, Xhani S, Gumpper RH, Luo M, Wilson WD, Steidl U^#, Poon GMK^#.
DNA selection by the master transcription factor PU.1.
Cell Rep. 2023; 42(7):112671.

Piszczatowski RT*, Schwenger E*, Sundaravel S, Stein CM, Liu Y, Stanley P, Verma A, Zheng D, Seidel RD, Almo SC, Townley RA^#, Bülow HE^#, Steidl U^#.
A glycan-based approach to cell characterization and isolation: Hematopoiesis as a paradigm.
J Exp Med. 2022; 219(11):e20212552.

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.
MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.
Cancer Cell. 2021; 39:529-547

Wheat JC, Sella Y, Willcockson M, Skoultchi AI, Bergman A, Singer RH, Steidl U.
Single Molecule Imaging of Transcription Dynamics in Somatic Stem Cells.
Nature. 2020; 583:431-436

Chen J, Kao YR, Sun D, Todorova TI, Reynolds D, Narayanagari SR, Montagna C, Will B, Verma A*, Steidl U*.
Myelodysplastic Syndrome Progression to Acute Myeloid Leukemia at the Stem Cell Level.
Nat Med. 2019; 25:103-110

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.
IL1RAP Potentiates Multiple Oncogenic Signaling Pathways in AML.
J Exp Med. 2018; 215:1709-1727

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.
Dual inhibition of MDMX and MDM2 as a Therapeutic Strategy in Leukemia.
Science Transl Med. 2018 Apr 11; 10:eaao3003

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.
Pharmacological Inhibition of the Transcription Factor PU.1 in Leukemia.
J Clin Invest. 2017; 127:4297-4313

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. 
A Myeloid Tumor Suppressor Role for NOL3. 
J Exp Med. 2017; 214:753-771

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.
New IDH1 Mutant Inhibitors for Treatment of Acute Myeloid Leukemia.
Nat Chem Biol. 2015; 11:878-886

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.
Minimal PU.1 Reduction Induces a Preleukemic State and Promotes Development of Acute Myeloid Leukemia.
Nat Med. 2015; 21:1172-1181

Pandolfi A*, Stanley RF*, Yu Y, Bartholdy B, Pendurti G, Gritsman K, Boultwood J, Chernoff J, Verma A, Steidl U.
PAK1 is a Therapeutic Target in Acute Myeloid Leukemia and Myelodysplastic Syndrome.
Blood. 2015; 126:1118-27

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^#, Steidl U^#.
A human hematopoietic stem cell-commitment related DNA cytosine methylation signature is prognostic for overall survival in acute myeloid leukemia.     
J Clin Invest. 2014; 124:1158-1167

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.
Special AT-rich Sequence-Binding Protein 1 (Satb1) regulates hematopoietic stem cell self-renewal by promoting quiescence and repressing differentiation commitment.
Nat Immunol. 2013; 14:437-45

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.
H2.0-like Homeobox (HLX) Regulates Early Hematopoiesis and Promotes Acute Myeloid Leukemia.
Cancer Cell. 2012; 22:194–208

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*.
Stem and progenitor cells in myelodysplastic syndromes show aberrant stage specific expansion and harbor genetic and epigenetic alterations.
Blood. 2012; 120:2076-2086

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.
Overexpression of interleukin 1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS.
Blood. 2012; 120:1290-1298

Roth M, Will B, Simkin G, Rao S, Barreyro L, Bartholdy B, Tamari R, Mitsiades CS, Verma A, Steidl U.
Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation.
Blood. 2012; 120:386-394

Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U.
Effect of the nonpeptide thrombopoetin receptor agnoist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome.
Blood. 2009; 114:3899-3908

Review Articles and Commentaries:

Taylor SJ, Steidl U.
Chemical restriction of PU.1 genomic binding sites activates alternate gene networks.
Nat Genet. 2024; doi.org/10.1038/s41588-024-01912-6

Piszczatowski RT, Buelow HE, Steidl U.
Heparan sulfates and heparan sulfate proteoglycans in hematopoiesis.
Blood. 2024; 143:2571-2587

Wheat JC, Steidl U.
Posttranscriptional Arid3a Deregulation in AMKL.
Blood. 2022; 139:637-638

Tatsumi G, Steidl U.
Transcriptional circuit dynamics in HSPC.
Blood. 2021; 138:1382-1384

Taylor SJ, Sundaravel S, Steidl U.
Exploting a key transcriptional dependency: ZMYND8 and IRF8 in AML.
Mol Cell. 2021; 81:3445-3446

Wheat JC, Steidl U.
Gene expression at a single molecule level: Implications for MDS and AML.
Blood. 2021; 138:625-636

Ueda K, Steidl U.
Epigenetic Achilles' heel of AML.
Nature Cancer. 2021; 2:481-483

Schwenger E, Steidl U.
An evolutionary approach to clonally complex hematologic disorders.
Blood Cancer Discov. 2021 May;2(3):201-215.

Sundaravel S, Steidl U.
Stem cell origins of JMML.
J Exp Med. 2021; 218:e20202152

Stauber J, Greally JM, Steidl U.
Preleukemic and leukemic evolution at the stem cell level.
Blood. 2021; 137:1013-1018

Ueda K, Kumari R, Steidl U.
Fueling clonal dominance through TRAFficking of NF-kB signaling.
Nat Immunol. 2020; 21:489-490

Mitchell K, Steidl U.
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).
Cold Spring Harb Perspect Med. 2020; 10:a036251

Piszczatowski RT, Steidl U.
Aurora Kinase A Inhibition: A Mega-Hit for Myelofibrosis Therapy?
Clin Cancer Res. 2019; 25:4868-4870

Chen J, Steidl U.
Inhibition of HIF1α Signaling: A Grand Slam for MDS Therapy ?
Cancer Discovery. 2018; 8:1355-1357

Wheat JC, Steidl U.
Linking histone methylation, transcription rates, and stem cell robustness.
Haematologica. 2018; 103:1093

Taylor SJ, Steidl U.
Metabolic strugGLS after FLT3 inhibition in AML.
Blood. 2018; 131:1631-1632

Wheat JC, Steidl U. 
ETO2-GLIS2: A chimeric transcription factor drives leukemogenesis through a neomorphic transcription network.
Cancer Cell. 2017; 31:307-308

Shastri A, Will B, Steidl U*, Verma A*. Stem and Progenitor Cell Alterations in Myelodysplastic Syndromes.
Blood. 2017; 129:1586-1594

Carvajal L, Steidl U. Eliminating cancer stem cells in CML with combination transcriptional therapy.
Cell Stem Cell. 2016; 19:6-8 

Stanley RF, Steidl U. Molecular mechanism of mutant CALR-mediated transformation.
Cancer Discovery. 2016; 6:344-346

Stanley RF, Steidl U. Ectopic Dnmt3b Expression Delays Leukemogenesis.
Blood. 2016; 127:1525-6

Antony-Debre I, Steidl U.
Functionally relevant RNA helicase mutations in familial and sporadic myeloid malignancies.
Cancer Cell. 2015; 27:609-611

Verma A, Steidl U.
A synthetic lethal approach targeting mutant isocitrate dehydrogenase in acute myeloid leukemia.
Nat Med. 2015;21:113-114

Will B, Steidl U.
Combinatorial haplo-deficient tumor suppression in 7q-deficient myelodysplastic syndrome and acute myeloid leukemia.
Cancer Cell. 2014; 25:555-557

Will B, Steidl U.
Stem cell fate regulation by dynein motor protein Lis1.
Nat Genet. 2014; 46:217-218

Antony-Debre I, Steidl U.
CDK6, a new target in MLL-driven leukemia.
Blood. 2014; 124:5-6

Elias HK, Schinke C, Bhattacharyya S, Will B, Verma A, Steidl U.
Stem cell origin of myelodysplastic syndromes.
Oncogene. 2013 Dec 16. doi: 10.1038/onc.2013.520

Pandolfi A, Barreyro L, Steidl U.
Pre-leukemic stem cells: molecular biology and clinical implications of the precursors to leukemia stem cells.
Stem Cells Transl Med. 2013; 2:143–150