Publications by authors named "Ulrich Steidl"

126 Publications

MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.

Cancer Cell 2021 Apr 4;39(4):529-547.e7. Epub 2021 Mar 4.

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY 10461, USA; Blood Cancer Institute, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY 10461, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY 10461, USA. Electronic address:

MDMX is overexpressed in the vast majority of patients with acute myeloid leukemia (AML). We report that MDMX overexpression increases preleukemic stem cell (pre-LSC) number and competitive advantage. Utilizing five newly generated murine models, we found that MDMX overexpression triggers progression of multiple chronic/asymptomatic preleukemic conditions to overt AML. Transcriptomic and proteomic studies revealed that MDMX overexpression exerts this function, unexpectedly, through activation of Wnt/β-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1α and leads to accumulation of β-Catenin in a p53-independent manner. Wnt/β-Catenin inhibitors reverse MDMX-induced pre-LSC properties, and synergize with MDMX-p53 inhibitors. Wnt/β-Catenin signaling correlates with MDMX expression in patients with preleukemic myelodysplastic syndromes and is associated with increased risk of progression to AML. Our work identifies MDMX overexpression as a pervasive preleukemic-to-AML transition mechanism in different genetically driven disease subtypes, and reveals Wnt/β-Catenin as a non-canonical MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception.
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http://dx.doi.org/10.1016/j.ccell.2021.02.006DOI Listing
April 2021

Epigenetic modifiers in normal and aberrent erythropoeisis.

Semin Hematol 2021 Jan 29;58(1):15-26. Epub 2020 Dec 29.

Department of Medicine, University of Chicago, Chicago, IL. Electronic address:

Erythroid differentiation program is comprised of lineage commitment, erythroid progenitor proliferation, and termination differentiation. Each stage of the differentiation program is heavily influenced by epigenetic modifiers that alter the epigenome in a dynamic fashion influenced by cytokines/humeral factors and are amicable to target by drugs. The epigenetic modifiers can be classified as DNA modifiers (DNMT, TET), mRNA modifiers (RNA methylases and demethylases) and histone protein modifiers (methyltransferases, acetyltransferases, demethylases, and deacetylases). Here we describe mechanisms by which these epigenetic modifiers influence and guide erythroid-lineage differentiation during normal and malignant erythropoiesis and also benign diseases that arise from their altered structure or function.
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http://dx.doi.org/10.1053/j.seminhematol.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883935PMC
January 2021

Stem cell origins of JMML.

J Exp Med 2021 Feb;218(2)

Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY.

In this issue of JEM, Louka et al. (https://doi.org/10.1084/jem.20180853) report that leukemia stem cells lie within the phenotypic hematopoietic stem cell and progenitor cell compartments in juvenile myelomonocytic leukemia (JMML). Furthermore, they identify several candidate biomarker/therapeutic targets, such as CD96 and SLC2A1, that are of translational significance in JMML.
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http://dx.doi.org/10.1084/jem.20202152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802372PMC
February 2021

Case report of combination therapy with Azacytidine, Enasidenib and Venetoclax in primary refractory AML.

Exp Hematol Oncol 2021 Jan 4;10(1). Epub 2021 Jan 4.

Albert Einstein College of Medicine, Department of Hematology/Oncology, Bronx, NY, USA.

Optimal treatment of acute myeloid leukemia (AML) arising in elderly patients remains a challenge. FDA approval of Ivosidenib and Enasidenib, small molecule inhibitors of isocitrate dehydrogenase enzymes (IDH1 and 2) have opened new avenues of treatment. We present a 60-year-old woman with refractory AML, achieving complete response to the combination therapy of hypomethylating agent, Azacytidine with the IDH2 inhibitor, Enasidenib, and BCL2 inhibitor, Venetoclax. To our knowledge, this is the first case report of a patient with IDH2 mutated refractory AML achieving complete response to combination therapy with azacytidine, enasidenib and venetoclax.
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http://dx.doi.org/10.1186/s40164-020-00186-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784272PMC
January 2021

Preleukemic and leukemic evolution at the stem cell level.

Blood 2021 Feb;137(8):1013-1018

Albert Einstein College of Medicine-Montefiore Health System, The Bronx, NY.

Hematological malignancies are an aggregate of diverse populations of cells that arise following a complex process of clonal evolution and selection. Recent approaches have facilitated the study of clonal populations and their evolution over time across multiple phenotypic cell populations. In this review, we present current concepts on the role of clonal evolution in leukemic initiation, disease progression, and relapse. We highlight recent advances and unanswered questions about the contribution of the hematopoietic stem cell population to these processes.
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http://dx.doi.org/10.1182/blood.2019004397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907728PMC
February 2021

A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy.

Nat Cancer 2020 Mar 2;1(3):315-328. Epub 2020 Mar 2.

Department of Medicine, Albert Einstein College of Medicine, Bronx NY, USA.

Doxorubicin remains an essential component of many cancer regimens, but its use is limited by lethal cardiomyopathy, which has been difficult to target, owing to pleiotropic mechanisms leading to apoptotic and necrotic cardiac cell death. Here we show that BAX is rate-limiting in doxorubicin-induced cardiomyopathy and identify a small-molecule BAX inhibitor that blocks both apoptosis and necrosis to prevent this syndrome. By allosterically inhibiting BAX conformational activation, this compound blocks BAX translocation to mitochondria, thereby abrogating both forms of cell death. When co-administered with doxorubicin, this BAX inhibitor prevents cardiomyopathy in zebrafish and mice. Notably, cardioprotection does not compromise the efficacy of doxorubicin in reducing leukemia or breast cancer burden in vivo, primarily due to increased priming of mitochondrial death mechanisms and higher BAX levels in cancer cells. This study identifies BAX as an actionable target for doxorubicin-induced cardiomyopathy and provides a prototype small-molecule therapeutic.
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http://dx.doi.org/10.1038/s43018-020-0039-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413180PMC
March 2020

Single-molecule imaging of transcription dynamics in somatic stem cells.

Nature 2020 07 24;583(7816):431-436. Epub 2020 Jun 24.

Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.

Molecular noise is a natural phenomenon that is inherent to all biological systems. How stochastic processes give rise to the robust outcomes that support tissue homeostasis remains unclear. Here we use single-molecule RNA fluorescent in situ hybridization (smFISH) on mouse stem cells derived from haematopoietic tissue to measure the transcription dynamics of three key genes that encode transcription factors: PU.1 (also known as Spi1), Gata1 and Gata2. We find that infrequent, stochastic bursts of transcription result in the co-expression of these antagonistic transcription factors in the majority of haematopoietic stem and progenitor cells. Moreover, by pairing smFISH with time-lapse microscopy and the analysis of pedigrees, we find that although individual stem-cell clones produce descendants that are in transcriptionally related states-akin to a transcriptional priming phenomenon-the underlying transition dynamics between states are best captured by stochastic and reversible models. As such, a stochastic process can produce cellular behaviours that may be incorrectly inferred to have arisen from deterministic dynamics. We propose a model whereby the intrinsic stochasticity of gene expression facilitates, rather than impedes, the concomitant maintenance of transcriptional plasticity and stem cell robustness.
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http://dx.doi.org/10.1038/s41586-020-2432-4DOI Listing
July 2020

The thrombopoietin mimetic JNJ-26366821 increases megakaryopoiesis without affecting malignant myeloid proliferation.

Leuk Lymphoma 2020 10 24;61(10):2453-2465. Epub 2020 Jun 24.

Department of Oncology, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.

Thrombocytopenia remains a challenge in myeloid malignancies, needing safer and more effective therapies. JNJ-26366821, a pegylated synthetic peptide thrombopoietin (TPO) mimetic not homologous to endogenous TPO, has an in-vitro EC50 of 0.2 ng/mL for the TPO receptor and dose dependently elevates platelets in volunteers. We demonstrate that JNJ-26366821 increases megakaryocytic differentiation and megakaryocytic colony formation in healthy controls and samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). JNJ-26366821 had no effect on proliferation of malignant myeloid cell lines at doses up to 1000 ng/mL and malignant patient-derived mononuclear cells showed no increased cell growth or leukemic colony formation capacity at concentrations between 0.2 ng/mL and 10 ng/mL. Furthermore, JNJ-26366821 did not enhance in-vivo engraftment of leukemic cells in an AML xenotransplantation murine model. Our results show that JNJ-26366821 stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clones in MDS/AML and provides the rationale for clinical testing of JNJ-26366821 in myeloid malignancies.
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http://dx.doi.org/10.1080/10428194.2020.1775213DOI Listing
October 2020

H1 linker histones silence repetitive elements by promoting both histone H3K9 methylation and chromatin compaction.

Proc Natl Acad Sci U S A 2020 06 8;117(25):14251-14258. Epub 2020 Jun 8.

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461;

Nearly 50% of mouse and human genomes are composed of repetitive sequences. Transcription of these sequences is tightly controlled during development to prevent genomic instability, inappropriate gene activation and other maladaptive processes. Here, we demonstrate an integral role for H1 linker histones in silencing repetitive elements in mouse embryonic stem cells. Strong H1 depletion causes a profound de-repression of several classes of repetitive sequences, including major satellite, LINE-1, and ERV. Activation of repetitive sequence transcription is accompanied by decreased H3K9 trimethylation of repetitive sequence chromatin. H1 linker histones interact directly with Suv39h1, Suv39h2, and SETDB1, the histone methyltransferases responsible for H3K9 trimethylation of chromatin within these regions, and stimulate their activity toward chromatin in vitro. However, we also implicate chromatin compaction mediated by H1 as an additional, dominant repressive mechanism for silencing of repetitive major satellite sequences. Our findings elucidate two distinct, H1-mediated pathways for silencing heterochromatin.
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http://dx.doi.org/10.1073/pnas.1920725117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322038PMC
June 2020

Fueling clonal dominance through TRAFficking of NF-κB signaling.

Nat Immunol 2020 05;21(5):489-490

Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.

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http://dx.doi.org/10.1038/s41590-020-0662-0DOI Listing
May 2020

Mechanisms and therapeutic prospects of thrombopoietin receptor agonists.

Semin Hematol 2019 10 19;56(4):262-278. Epub 2019 Oct 19.

Albert Einstein College of Medicine, New York, NY. Electronic address:

The second-generation thrombopoietin (TPO) receptor agonists eltrombopag and romiplostim are potent activators of megakaryopoiesis and represent a growing treatment option for patients with thrombocytopenic hematological disorders. Both TPO receptor agonists have been approved worldwide for the treatment of children and adults with chronic immune thrombocytopenia. In the EU and USA, eltrombopag is approved for the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy and in the USA for the first-line treatment of severe aplastic anemia in combination with immunosuppressive therapy. Eltrombopag has also shown efficacy in several other disease settings, for example, chemotherapy-induced thrombocytopenia, selected inherited thrombocytopenias, and myelodysplastic syndromes. While both TPO receptor agonists stimulate TPO receptor signaling and enhance megakaryopoiesis, their vastly different biochemical structures bestow upon them markedly different molecular and functional properties. Here, we review and discuss results from preclinical and clinical studies on the functional and molecular mechanisms of action of this new class of drug.
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http://dx.doi.org/10.1053/j.seminhematol.2019.09.001DOI Listing
October 2019

Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias.

Blood Adv 2019 12;3(23):3962-3967

Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.

Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of overt leukemia. Rigorous sorting, followed by targeted sequencing, resulted in ultradeep functional depth of sequencing and revealed preexisting mutant hematopoietic stem cell (HSC) clones, mainly harboring TP53 mutations, that became the dominant population at the time of leukemic presentation. Taken together, these data show that HSCs can act as reservoirs for leukemia-initiating cells many years before the onset of myeloid leukemia.
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http://dx.doi.org/10.1182/bloodadvances.2019000731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963234PMC
December 2019

Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts.

Elife 2019 11 1;8. Epub 2019 Nov 1.

Rutgers University, New Brunswick, United States.

Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including . Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CX. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation.
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http://dx.doi.org/10.7554/eLife.50663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874475PMC
November 2019

Phase II Study of the ALK5 Inhibitor Galunisertib in Very Low-, Low-, and Intermediate-Risk Myelodysplastic Syndromes.

Clin Cancer Res 2019 12 3;25(23):6976-6985. Epub 2019 Sep 3.

Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

Purpose: Overactivation of TGF-β signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-β receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies.

Patients And Methods: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin ≤ 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off.

Results: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4-40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%).

Conclusions: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1338DOI Listing
December 2019

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 01 2;10(1). Epub 2020 Jan 2.

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Therapies targeting cell-surface antigens in acute myeloid leukemia (AML) have been tested over the past 20 years with limited improvement in overall survival. Recent advances in the understanding of AML pathogenesis support therapeutic targeting of leukemia stem cells as the most promising avenue toward a cure. In this review, we provide an overview of the evolving leukemia stem cell (LSC) model, including evidence of the cell of origin, cellular and molecular disease architecture, and source of relapse in AML. In addition, we explore limitations of current targeted strategies utilized in AML and describe the various immunophenotypic antigens that have been proposed as LSC-directed therapeutic targets. We draw lessons from current approaches as well as from the (pre)-LSC model to suggest criteria that immunophenotypic targets should meet for more specific and effective elimination of disease-initiating clones, highlighting in detail a few targets that we suggest fit these criteria most completely.
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http://dx.doi.org/10.1101/cshperspect.a036251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938655PMC
January 2020

Runx1 promotes murine erythroid progenitor proliferation and inhibits differentiation by preventing Pu.1 downregulation.

Proc Natl Acad Sci U S A 2019 09 20;116(36):17841-17847. Epub 2019 Aug 20.

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461;

Pu.1 is an ETS family transcription factor (TF) that plays critical roles in erythroid progenitors by promoting proliferation and blocking terminal differentiation. However, the mechanisms controlling expression and down-regulation of Pu.1 during early erythropoiesis have not been defined. In this study, we identify the actions of Runx1 and Pu.1 itself at the Pu.1 gene Upstream Regulatory Element (URE) as major regulators of Pu.1 expression in Burst-Forming Unit erythrocytes (BFUe). During early erythropoiesis, Runx1 and Pu.1 levels decline, and chromatin accessibility at the URE is lost. Ectopic expression of Runx1 or Pu.1, both of which bind the URE, prevents Pu.1 down-regulation and blocks terminal erythroid differentiation, resulting in extensive ex vivo proliferation and immortalization of erythroid progenitors. Ectopic expression of Runx1 in BFUe lacking a URE fails to block terminal erythroid differentiation. Thus, Runx1, acting at the URE, and Pu.1 itself directly regulate Pu.1 levels in erythroid cells, and loss of both factors is critical for Pu.1 down-regulation during terminal differentiation. The molecular mechanism of URE inactivation in erythroid cells through loss of TF binding represents a distinct pattern of Pu.1 regulation from those described in other hematopoietic cell types such as T cells which down-regulate Pu.1 through active repression. The importance of down-regulation of Runx1 and Pu.1 in erythropoiesis is further supported by genome-wide analyses showing that their DNA-binding motifs are highly overrepresented in regions that lose chromatin accessibility during early erythroid development.
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http://dx.doi.org/10.1073/pnas.1901122116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731665PMC
September 2019

Misidentification of and other mutations in cancer due to highly homologous genomic regions.

Leuk Lymphoma 2019 12 10;60(13):3132-3137. Epub 2019 Jul 10.

Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.

The gene has been shown to be recurrently mutated in many malignancies including in families with acute myeloid leukemia. We demonstrate that many variant calls made by exome sequencing are false positives due to misalignment to homologous regions, including a region on chr21, and can only be validated by long-range PCR. Numerous other recurrently mutated genes reported in COSMIC and TCGA databases have pseudogenes and cannot also be validated by conventional short read-based sequencing approaches. Genome-wide identification of pseudogene regions demonstrates that frequency of these homologous regions is increased with sequencing read lengths below 200 bps. To enable identification of poor quality sequencing variants in prospective studies, we generated novel genome-wide maps of regions with poor mappability that can be used in variant calling algorithms. Taken together, our findings reveal that pseudogene regions are a source of false-positive mutations in cancers.
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http://dx.doi.org/10.1080/10428194.2019.1630620DOI Listing
December 2019

HIV portends a poor prognosis in myelodysplastic syndromes.

Leuk Lymphoma 2019 12 8;60(14):3529-3535. Epub 2019 Jul 8.

Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.

Even though HIV is associated with worse prognosis in many malignancies, the clinical course of myelodysplastic syndrome (MDS) in HIV + patients has not been well studied. Determining the clinical presentation and outcomes of MDS in these patients would be important for future diagnostic strategies, as anemia and other cytopenias are commonly seen in HIV + patients. Unique data mining software was used to identify cases of MDS or AML in adult patients who were also HIV + at Albert Einstein/Montefiore Medical Center between 1 January 2003 and 1 January 2017. Using Chi-Square and Fisher's exact test, characteristics of the HIV + MDS patients were compared to 135 HIV - MDS patients from the same institution diagnosed between 1997 and 2011. Fourteen biopsy proven MDS patients were identified with concomitant HIV. HIV + MDS patients presented at a younger age (59 vs. 71 yrs,  = .001) had higher risk disease, faster progression to acute leukemia, and worse overall survival (median survival 11.2 vs. 69.1 mo,  < .001) compared to HIV - MDS controls. Additionally, there was a higher prevalence of clonal-hematopoiesis related mutations (ASXL1, DNMT3A) and a higher proportion of patients with high risk cytogenetics. Analysis of the largest single center cohort of HIV + MDS patients demonstrated that these individuals present at a significantly younger age and with higher risk disease than their HIV - counterparts.
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http://dx.doi.org/10.1080/10428194.2019.1633631DOI Listing
December 2019

Aurora Kinase A Inhibition: A Mega-Hit for Myelofibrosis Therapy?

Clin Cancer Res 2019 08 13;25(16):4868-4870. Epub 2019 Jun 13.

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York.

The positive but limited efficacy of JAK inhibitors has sparked the need for alternative therapeutic targets in the treatment of myelofibrosis. The discovery of novel targets, like Aurora Kinase A, may provide new avenues of single-agent and combinatorial therapy for myelofibrosis and restoration of normal bone marrow function..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697558PMC
August 2019

U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.

Nat Cell Biol 2019 05 22;21(5):640-650. Epub 2019 Apr 22.

Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Spliceosome mutations are common in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but the oncogenic changes due to these mutations have not been identified. Here a global analysis of exon usage in AML samples revealed distinct molecular subsets containing alternative spliced isoforms of inflammatory and immune genes. Interleukin-1 receptor-associated kinase 4 (IRAK4) was the dominant alternatively spliced isoform in MDS and AML and is characterized by a longer isoform that retains exon 4, which encodes IRAK4-long (IRAK4-L), a protein that assembles with the myddosome, results in maximal activation of nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) and is essential for leukaemic cell function. Expression of IRAK4-L is mediated by mutant U2 small nuclear RNA auxiliary factor 1 (U2AF1) and is associated with oncogenic signalling in MDS and AML. Inhibition of IRAK4-L abrogates leukaemic growth, particularly in AML cells with higher expression of the IRAK4-L isoform. Collectively, mutations in U2AF1 induce expression of therapeutically targetable 'active' IRAK4 isoforms and provide a genetic link to activation of chronic innate immune signalling in MDS and AML.
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http://dx.doi.org/10.1038/s41556-019-0314-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679973PMC
May 2019

Transcriptional regulators CITED2 and PU.1 cooperate in maintaining hematopoietic stem cells.

Exp Hematol 2019 05 13;73:38-49.e7. Epub 2019 Apr 13.

Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address:

Reduced expression of the transcription factor PU.1 is frequently associated with development of acute myeloid leukemia (AML), whereas elevated levels of CITED2 (CBP/p300-interacting-transactivator-with-an-ED-rich-tail 2) enhance maintenance of both normal and leukemic hematopoietic stem and progenitor cells (HSPCs). Recent findings indicate that PU.1 and CITED2 act in the same gene regulatory network. We therefore examined a potential synergistic effect of simultaneous PU.1 downregulation and CITED2 upregulation on stem cell biology and AML pathogenesis. We found that simultaneous PU.1/CITED2 deregulation in human CD34 cord blood (CB) cells, as well as CITED2 upregulation in preleukemic murine PU.1-knockdown (PU.1) bone marrow cells, significantly increased the maintenance of HSPCs compared with the respective deregulation of either factor alone. Increased replating capacity of PU.1/CITED2 cells in in vitro assays eventually resulted in outgrowth of transformed cells, while upregulation of CITED2 in PU.1 cells enhanced their engraftment in in vivo transplantation studies without affecting leukemic transformation. Transcriptional analysis of CD34 CB cells with combined PU.1/CITED2 alterations revealed a set of differentially expressed genes that highly correlated with gene signatures found in various AML subtypes. These findings illustrate that combined PU.1/CITED2 deregulation induces a transcriptional program that promotes HSPC maintenance, which might be a prerequisite for malignant transformation.
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http://dx.doi.org/10.1016/j.exphem.2019.03.003DOI Listing
May 2019

Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis.

Cancer Discov 2019 06 3;9(6):778-795. Epub 2019 Apr 3.

Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.

Even though the Ten-eleven translocation (TET) enzymes catalyze the generation of 5-hydroxymethylcytosines required for lineage commitment and subsequent differentiation of stem cells into erythroid cells, the mechanisms that link extracellular signals to TET activation and DNA hydroxymethylation are unknown. We demonstrate that hematopoietic cytokines phosphorylate TET2, leading to its activation in erythroid progenitors. Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin. The activating JAK2 mutation seen in myeloproliferative disease patient samples and in mouse models is associated with increased TET activity and cytosine hydroxymethylation as well as genome-wide loss of cytosine methylation. These epigenetic and functional changes are also associated with increased expression of several oncogenic transcripts. Thus, we demonstrate that JAK2-mediated TET2 phosphorylation provides a mechanistic link between extracellular signals and epigenetic changes during hematopoiesis. SIGNIFICANCE: Identification of TET2 phosphorylation and activation by cytokine-stimulated JAK2 links extracellular signals to chromatin remodeling during hematopoietic differentiation. This provides potential avenues to regulate TET2 function in the context of myeloproliferative disorders and myelodysplastic syndromes associated with the JAK2-activating mutation..
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http://dx.doi.org/10.1158/2159-8290.CD-18-1138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697164PMC
June 2019

PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma.

Clin Cancer Res 2019 06 12;25(12):3589-3601. Epub 2019 Mar 12.

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York.

Purpose: To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models.

Experimental Design: Frequency and prognostic impact of amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and xenograft models were developed using primary ATLL cells from North American patients. Two PAK inhibitors were used to block PAK kinase activity pharmacologically. siRNA-based gene silencing approach was used to genetically knockdown (KD) PAK1 and PAK2 in ATLL cell lines.

Results: PAK1/2/4 are the three most abundantly expressed PAK family members in ATLL. amplifications are seen in 24% of ATLLs and are associated with worse prognosis in a large patient cohort. The pan-PAK inhibitor PF-3758309 (PF) has strong and activity in a variety of ATLL preclinical models. These activities of PF are likely attributed to its ability to target several PAK isoforms simultaneously because genetic silencing of either PAK1 or PAK2 produced more modest effects. PAK2 plays a major role in CADM1-mediated stromal interaction, which is an important step in systemic dissemination of the disease. This finding is consistent with the observation that amplification is more frequent in aggressive ATLLs and correlates with inferior outcome.

Conclusions: PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Taken together, PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3033DOI Listing
June 2019

Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma.

J Clin Invest 2019 03 4;129(4):1612-1625. Epub 2019 Mar 4.

Albert Einstein College of Medicine, Montefiore Medical Center, New York, New York, USA.

Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by l-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome-wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high-dose AA in ccRCC.
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http://dx.doi.org/10.1172/JCI98747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436862PMC
March 2019

Publisher Correction: Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level.

Nat Med 2019 Mar;25(3):529

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.

In the version of this article originally published, Ulrich Steidl's name was listed as "and Ulrich Steidl." His name has been updated to "Ulrich Steidl." The error has been fixed in the print, PDF and HTML versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0333-yDOI Listing
March 2019

Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level.

Nat Med 2019 01 3;25(1):103-110. Epub 2018 Dec 3.

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.

Myelodysplastic syndromes (MDS) frequently progress to acute myeloid leukemia (AML); however, the cells leading to malignant transformation have not been directly elucidated. As progression of MDS to AML in humans provides a biological system to determine the cellular origins and mechanisms of neoplastic transformation, we studied highly fractionated stem cell populations in longitudinal samples of patients with MDS who progressed to AML. Targeted deep sequencing combined with single-cell sequencing of sorted cell populations revealed that stem cells at the MDS stage, including immunophenotypically and functionally defined pre-MDS stem cells (pre-MDS-SC), had a significantly higher subclonal complexity compared to blast cells and contained a large number of aging-related variants. Single-cell targeted resequencing of highly fractionated stem cells revealed a pattern of nonlinear, parallel clonal evolution, with distinct subclones within pre-MDS-SC and MDS-SC contributing to generation of MDS blasts or progression to AML, respectively. Furthermore, phenotypically aberrant stem cell clones expanded during transformation and stem cell subclones that were not detectable in MDS blasts became dominant upon AML progression. These results reveal a crucial role of diverse stem cell compartments during MDS progression to AML and have implications for current bulk cell-focused precision oncology approaches, both in MDS and possibly other cancers that evolve from premalignant conditions, that may miss pre-existing rare aberrant stem cells that drive disease progression and leukemic transformation.
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http://dx.doi.org/10.1038/s41591-018-0267-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436966PMC
January 2019

Inhibition of HIF1α Signaling: A Grand Slam for MDS Therapy?

Cancer Discov 2018 11;8(11):1355-1357

Department of Cell Biology, and Department of Medicine (Oncology), Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, New York.

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http://dx.doi.org/10.1158/2159-8290.CD-18-1061DOI Listing
November 2018

Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells.

J Clin Invest 2018 12 5;128(12):5479-5488. Epub 2018 Nov 5.

AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated overexpression of STAT3 that was validated in an independent cohort. STAT3 overexpression was predictive of a shorter survival and worse clinical features in a large MDS cohort. High STAT3 expression signature in MDS CD34+ cells was similar to known preleukemic gene signatures. Functionally, STAT3 inhibition by a clinical, antisense oligonucleotide, AZD9150, led to reduced viability and increased apoptosis in leukemic cell lines. AZD9150 was rapidly incorporated by primary MDS/AML stem and progenitor cells and led to increased hematopoietic differentiation. STAT3 knockdown also impaired leukemic growth in vivo and led to decreased expression of MCL1 and other oncogenic genes in malignant cells. These studies demonstrate that STAT3 is an adverse prognostic factor in MDS/AML and provide a preclinical rationale for studies using AZD9150 in these diseases.
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http://dx.doi.org/10.1172/JCI120156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264739PMC
December 2018

Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag.

Sci Transl Med 2018 09;10(458)

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Eltrombopag (EP), a small-molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy in stimulating sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. Although the functional and molecular effects of EP on megakaryopoiesis have been studied in the past, mechanistic insights into its effects on the earliest stages of hematopoiesis have been limited. We investigated the effects of EP treatment on hematopoietic stem cell (HSC) function using purified primary HSCs in separation-of-function mouse models, including a TPO-R-deficient strain, and stem cells isolated from patients undergoing TPO-R agonist treatment. Our mechanistic studies showed a stimulatory effect on stem cell self-renewal independently of TPO-R. Human and mouse HSCs responded to acute EP treatment with metabolic and gene expression alterations consistent with a reduction of intracellular labile iron pools that are essential for stem cell maintenance. Iron preloading prevented the stem cell stimulatory effects of EP. Moreover, comparative analysis of stem cells in the bone marrow of patients receiving EP showed a marked increase in the number of functional stem cells compared to patients undergoing therapy with romiplostim, another TPO-R agonist lacking an iron-chelating ability. Together, our study demonstrates that EP stimulates hematopoiesis at the stem cell level through iron chelation-mediated molecular reprogramming and indicates that labile iron pool-regulated pathways can modulate HSC function.
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http://dx.doi.org/10.1126/scitranslmed.aas9563DOI Listing
September 2018

Linking histone methylation, transcription rates, and stem cell robustness.

Haematologica 2018 07;103(7):1093

Department of Cell Biology, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, NY, USA.

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http://dx.doi.org/10.3324/haematol.2018.196089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029540PMC
July 2018