Publications by authors named "Łukasz Gondek"

40 Publications

Clonal hematopoiesis and bone marrow failure syndromes.

Best Pract Res Clin Haematol 2021 06 25;34(2):101273. Epub 2021 May 25.

Department of Oncology, Division of Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Electronic address:

Bone marrow failure syndromes (BMF) are a group of conditions characterized by inefficient hematopoiesis frequently associated with extra-hematopoietic phenotypes and variable risk of progression to myeloid malignancies. They can be acquired or inherited and mediated by either cell extrinsic factors or cell intrinsic impairment of hematopoietic stem cell (HSC) function. The pathophysiology includes immune-mediated attack (e.g., acquired BMFs) or germline defects in DNA damage repair machinery, telomeres maintenance or ribosomes biogenesis. (e.g., inherited BMF). Clonal hematopoiesis (CH) that frequently accompanies BMF may provide a mechanism of improved HSC fitness through the evasion of extracellular pressure or somatic reversion of germline defects. The mechanism for the CH selective advantage differs depending on the condition in which it occurs. However, this adaptation mechanism, particularly when involving putative oncogenes or tumor suppressors, may lead to increased risk of myeloid malignancies. Surveillance and early detection of leukemogenic clones may lead to timely implementation of curative therapies and improved survival.
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http://dx.doi.org/10.1016/j.beha.2021.101273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374084PMC
June 2021

Analysis of the Crystallization Kinetics and Thermal Stability of the Amorphous MgZnCa Alloy.

Materials (Basel) 2021 Jun 26;14(13). Epub 2021 Jun 26.

Institute of Metallurgy and Materials Science of Polish Academy of Sciences in Cracow, 25 Reymonta Street, 30-059 Cracow, Poland.

The aim of this study was to analyze the crystallization of the MgZnCa metallic glass alloy. The crystallization process of metallic glass MgZnCa was investigated by means of the differential scanning calorimetry. The glass-forming ability and crystallization are both strongly dependent on the heating rate. The crystallization kinetics, during the isothermal annealing, were modelled by the Johnson-Mehl-Avrami equation. Avrami exponents were from 2.7 to 3.51, which indicates diffusion-controlled grain growth. Local exponents of the Johnson-Mehl-Avrami equation were also calculated. In addition, the Mg phase-being the isothermal crystallization product-was found, and the diagram of the time-temperature phase transformation was developed. This diagram enables the reading of the start and end times of the crystallization process, occurring in amorphous ribbons of the MgZnCa alloy on the isothermal annealing temperature. The research showed high stability of the amorphous structure of MgZnCa alloy at human body temperature.
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http://dx.doi.org/10.3390/ma14133583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296845PMC
June 2021

On the Superconductivity Suppression in EuPrBaCuO.

Materials (Basel) 2021 Jun 23;14(13). Epub 2021 Jun 23.

Department of Solid State Physics, Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, A. Mickiewicza 30 Avenue, 30-059 Kraków, Poland.

This article reports on the non-trivial suppression of superconductivity in the EuPrBCO cuprates. As non-magnetic Eu ions are replaced by Pr carrying a magnetic moment, spin-related superconductivity loss can be expected. The research shows that the superconductivity disappearance for > 0.4 results from depletion of the carriers and their localization. The above conclusion was drawn by low-temperature X-ray diffraction analysis showing increased characteristic phonon frequencies with Pr content. This mechanism should promote electron-phonon coupling, at least for acoustic phonons. However, the inverse phenomenon was detected. Namely, there is a gradual deterioration of the optical phonons responsible for vibration of the Cu-O bonds with Pr increasing, as evidenced by Raman spectroscopy. Furthermore, the results of X-ray absorption spectroscopy precisely showed the location of the carriers for Pr-rich specimens. Finally, a schematic diagram for EuPrBCO is proposed to consolidate the presented research.
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http://dx.doi.org/10.3390/ma14133503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269594PMC
June 2021

Gender-related differences in the outcomes and genomic landscape of patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes.

Br J Haematol 2021 06 24;193(6):1142-1150. Epub 2021 May 24.

Division of Hematological Malignancies and Bone Marrow Transplantation, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes show a male predominance and men with MDS/MPN have worse outcomes, but it is unknown if the mutational burden differs between genders. We reviewed 167 patients with MDS/MPN and found that men had worse overall survival [hazard ratio (HR) 2·09, 95% confidence interval (CI) 1·16-3·75; P = 0·013] independent of subtype, Revised International Prognostic Scoring System score and age at diagnosis. We analysed the genomic data of a subset of 100 patients. Men had 0·88 more somatic mutations on average (95% CI 0·20-1·56, P = 0·011) independent of subtype, sample source and blast percentage. More somatic mutations was associated with a higher incidence of transformation to acute myeloid leukaemia (subdistribution HR 1·30, 95% CI 1·01-1·70; P = 0·046). Men had 0·70 more mutations in high-risk genes [additional sex combs like-1 (ASXL1), enhancer of zeste homolog 2 (EZH2), Runt-related transcription factor 1 (RUNX1), SET binding protein 1 (SETBP1), NRAS proto-oncogene, GTPase (NRAS), stromal antigen 2 (STAG2)] on average (95% CI 0·11-1·29, P = 0·021), and 13-times higher odds of harbouring an EZH2 mutation (95% CI 1·64-102·94, P = 0·015). The presence of an EZH2 mutation was associated with worse survival among men (HR 2·98, 95% CI 1·1-8·0; P = 0·031). Our present findings suggest that the worse outcomes in men with MDS/MPN are associated with a higher number of somatic mutations, especially in high-risk genes. These results warrant validation in larger cohorts and investigation of the underlying mechanisms.
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http://dx.doi.org/10.1111/bjh.17534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217263PMC
June 2021

Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features.

NPJ Precis Oncol 2021 May 14;5(1):38. Epub 2021 May 14.

Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), classified by a translocation between chromosomes 15 and 17 [t(15;17)], that is considered a true oncologic emergency though appropriate therapy is considered curative. Therapy is often initiated on clinical suspicion, informed by both clinical presentation as well as direct visualization of the peripheral smear. We hypothesized that genomic imprinting of morphologic features learned by deep learning pattern recognition would have greater discriminatory power and consistency compared to humans, thereby facilitating identification of t(15;17) positive APL. By applying both cell-level and patient-level classification linked to t(15;17) PML/RARA ground-truth, we demonstrate that deep learning is capable of distinguishing APL in both discovery and prospective independent cohort of patients. Furthermore, we extract learned information from the trained network to identify previously undescribed morphological features of APL. The deep learning method we describe herein potentially allows a rapid, explainable, and accurate physician-aid for diagnosing APL at the time of presentation in any resource-poor or -rich medical setting given the universally available peripheral smear.
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http://dx.doi.org/10.1038/s41698-021-00179-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121867PMC
May 2021

Whole-exome sequencing identifies functional classes of gene mutations associated with bone marrow failure in pediatric Fanconi Anemia patients.

Eur J Haematol 2021 Aug 24;107(2):293-294. Epub 2021 May 24.

Department of Pediatrics, Geisel School of Medicine at Dartmouth College, The Norris Cotton Cancer Center, Lebanon, NH, USA.

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http://dx.doi.org/10.1111/ejh.13645DOI Listing
August 2021

Omega Phase Formation in Ti-3wt.%Nb Alloy Induced by High-Pressure Torsion.

Materials (Basel) 2021 Apr 27;14(9). Epub 2021 Apr 27.

Institute of Metallurgy and Materials Science, Polish Academy of Sciences, 30-059 Krakow, Poland.

It is well known that severe plastic deformation not only leads to strong grain refinement and material strengthening but also can drive phase transformations. A study of the fundamentals of α → ω phase transformations induced by high-pressure torsion (HPT) in Ti-Nb-based alloys is presented in the current work. Before HPT, a Ti-3wt.%Nb alloy was annealed at two different temperatures in order to obtain the α-phase state with different amounts of niobium. X-ray diffraction analysis, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were applied for the characterisation of phase transitions and evolution of the microstructure. A small amount of the β-phase was found in the initial states, which completely transformed into the ω-phase during the HPT process. During HPT, strong grain refinement in the α-phase took place, as did partial transformation of the α- into the ω-phase. Therefore, two kinds of ω-phase, each with different chemical composition, were obtained after HPT. The first one was formed from the β-phase, enriched in Nb, and the second one from the α-phase. It was also found that the transformation of the α-phase into the ω-phase depended on the Nb concentration in the α-Ti phase. The less Nb there was in the α-phase, the more of the α-phase was transformed into the ω-phase.
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http://dx.doi.org/10.3390/ma14092262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123906PMC
April 2021

High-Entropy Perovskites as Multifunctional Metal Oxide Semiconductors: Synthesis and Characterization of (GdNdLaSmY)CoO.

ACS Appl Electron Mater 2020 Oct 18;2(10):3211-3220. Epub 2020 Sep 18.

Academic Centre for Materials and Nanotechnology, AGH University of Science and Technology, Al. Mickiewicza 30, 30059 Kraków, Poland.

Single-phase multicomponent perovskite-type cobalt oxide containing five cations in equiatomic amounts on the A-site, namely, (GdNdLaSmY)CoO, has been synthesized via the modified coprecipitation hydrothermal method. Using an original approach for heat treatment, which comprises quenching utilizing liquid nitrogen as a cooling medium, a single-phase ceramic with high configuration entropy, crystallizing in an orthorhombic distorted structure was obtained. It reveals the anomalous temperature dependence of the lattice expansion with two weak transitions at approx. 80 and 240 K that are assigned to gradual crossover from the low- via intermediate- to high-spin state of Co. The compound exhibits weak ferromagnetism at ≤ 10 K and signatures of antiferromagnetic correlations in the paramagnetic phase. Ab initio calculations predict a band gap Δ = 1.18 eV in the ground-state electronic structure with the dominant contribution of O_p and Co_d orbitals in the valence and conduction bands, respectively. Electronic transport measurements confirm the negative temperature coefficient of resistivity characteristic to a semiconducting material and reveal a sudden drop in activation energy at ∼ 240 K from ∼ 1 eV in the low-temperature phase to ∼ 0.3 eV at room temperature. The possibility of fine tuning of the semiconducting band gap via a subtle change in A-site stoichiometry is discussed.
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http://dx.doi.org/10.1021/acsaelm.0c00559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660934PMC
October 2020

Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide.

Blood Adv 2020 10;4(20):5078-5088

Division of Hematologic Malignancy and.

Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020002945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594402PMC
October 2020

Stem cell donors should be screened for CHIP.

Blood Adv 2020 02;4(4):784-788

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.

This article has a companion Counterpoint by Gibson and Lindsley.
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http://dx.doi.org/10.1182/bloodadvances.2019000394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042978PMC
February 2020

Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS.

Leukemia 2020 06 3;34(6):1563-1576. Epub 2020 Jan 3.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m/day IV continuous infusion days 1-3, daunorubicin 45 mg/m IV days 1-3, etoposide 400 mg/m IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4 and CD8 peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4 and CD8 T cells.
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http://dx.doi.org/10.1038/s41375-019-0693-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272276PMC
June 2020

Assessing clonal haematopoiesis: clinical burdens and benefits of diagnosing myelodysplastic syndrome precursor states.

Lancet Haematol 2020 Jan 3;7(1):e73-e81. Epub 2019 Dec 3.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Diagnosing, surveilling, and understanding the biological consequences of clonal haematopoiesis poses a clinical challenge for both patients and clinicians. The relationship between peripheral blood cytopenias and myeloid neoplasms-such as myelodysplastic syndrome-is an area of active research, and understanding of clonal haematopoiesis has developed markedly on the basis of findings concerning somatic mutations in genes known to be associated with myelodysplastic syndrome. These findings have raised the conundrum of how to appropriately define and follow myelodysplastic syndrome precursor states, such as clonal haematopoiesis of indeterminate potential (CHIP) and clonal cytopenias of undetermined significance (CCUS). Identifying these conditions could allow earlier diagnosis of myelodysplastic syndrome, modify surveillance for myelodysplastic syndrome, and possibly guide therapies, but this information also comes at a cost to patients that might or might not be justified by our present understanding of clonal haematopoiesis. When faced with a diagnosis of clonal haematopoiesis, some patients and providers might be content to let the events unfold naturally, whereas others may insist on intense follow-up and early interventions. This Viewpoint assesses recent developments in clonal haematopoiesis and the related implications for affected patients and their providers.
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http://dx.doi.org/10.1016/S2352-3026(19)30211-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008978PMC
January 2020

Hitting the bullseye with a nonlethal payload: resistance in CD123-positive malignancies.

Authors:
Lukasz P Gondek

J Clin Invest 2019 11;129(11):4590-4592

The interleukin 3 receptor (CD123) is a transmembrane protein that is absent or hardly expressed on normal hematopoietic stem cells, but highly expressed on the surface of cancer cells in several hematologic malignancies. In this issue of the JCI, Togami et al. investigated the mechanism of resistance to the recently approved anti-CD123 agent tagraxofusp, which consists of interleukin 3 fused to a truncated diphtheria toxin (DT) molecule. The authors demonstrated that loss of the intracellular target for DT, diphthamide, a conservative modification of histidine 715 in eukaryotic elongation factor 2, resulted in tagraxofusp resistance. Specifically, hypermethylation of the DPH1 gene, encoding a key enzyme in diphthamide synthesis, resulted in diphthamide loss. Notably, treatment with a DNA hypomethylating agent restored DPH1 expression and resensitized cells to tagraxofusp. The recognition of this resistance mechanism may have important clinical implications and lead to the development of more effective multiagent therapies.
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http://dx.doi.org/10.1172/JCI132443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819101PMC
November 2019

Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.

J Clin Invest 2019 08 8;129(11):4708-4723. Epub 2019 Aug 8.

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, and.

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.
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http://dx.doi.org/10.1172/JCI125022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819102PMC
August 2019

The diagnostic utility of targeted gene panel sequencing in discriminating etiologies of cytopenia.

Am J Hematol 2019 10 7;94(10):1141-1148. Epub 2019 Aug 7.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

The diagnostic utility of somatic mutations in the context of cytopenias is unclear: clonal hematopoiesis can be found in healthy individuals, patients with aplastic anemia (AA), clonal cytopenia of undetermined significance (CCUS) and myelodysplastic syndrome (MDS). We examined a cohort of 207 well-characterized cytopenic patients with a 640-gene next generation sequencing (NGS) panel and compared its diagnostic utility with a "virtual" 41 gene panel. The TET2, SF3B1, ASXL1, and TP53 were the most commonly mutated genes (frequency > 10%). Mutations in the 640-gene panel show high sensitivity (98.3%) but low specificity (47.6%) for diagnosis of MDS. Notably, mutations of splicing factors and genes in the RAS pathway are relatively specific to MDS. Furthermore, high variant allele frequency (VAF) predicts MDS: when the VAF is set at 20%, the positive predictive value (PPV) for MDS is 95.9%, with a specificity of 95.3%. The presence of two or more somatic mutations with ≥10% VAF showed a PPV of 95.2%. While the "virtual" 41-gene panel showed a mild decrease in sensitivity (95.7% vs 98.3%), 100% specificity was observed when either VAF was set at ≥20% (100% vs 95.3%), or two or more somatic mutations had VAFs ≥ 10%. Our study shows targeted gene panel sequencing improves the diagnostic approach and accuracy for unexplained cytopenia, with its high sensitivity and high PPV for MDS when applying VAF cutoffs. Furthermore, a 41-gene panel was shown to have at least comparable performance characteristics to the large 640-gene panel.
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http://dx.doi.org/10.1002/ajh.25592DOI Listing
October 2019

Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity.

Oncogene 2019 01 31;38(5):687-698. Epub 2018 Aug 31.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.
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http://dx.doi.org/10.1038/s41388-018-0431-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358463PMC
January 2019

Anthracycline-induced acute myocarditis and ventricular fibrillation arrest.

Am J Hematol 2018 03 18;93(3):469-470. Epub 2017 Dec 18.

Division of Hematologic Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.

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http://dx.doi.org/10.1002/ajh.24989DOI Listing
March 2018

Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.

Sci Transl Med 2015 Jun;7(291):291ra96

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations resulting in constitutive kinase activity are common in acute myeloid leukemia (AML) and carry a poor prognosis. Several agents targeting FLT3 have been developed, but their limited clinical activity suggests that the inhibition of other factors contributing to the malignant phenotype is required. We examined gene expression data sets as well as primary specimens and found that the expression of GLI2, a major effector of the Hedgehog (Hh) signaling pathway, was increased in FLT3-ITD compared to wild-type FLT3 AML. To examine the functional role of the Hh pathway, we studied mice in which Flt3-ITD expression results in an indolent myeloproliferative state and found that constitutive Hh signaling accelerated the development of AML by enhancing signal transducer and activator of transcription 5 (STAT5) signaling and the proliferation of bone marrow myeloid progenitors. Furthermore, combined FLT3 and Hh pathway inhibition limited leukemic growth in vitro and in vivo, and this approach may serve as a therapeutic strategy for FLT3-ITD AML.
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http://dx.doi.org/10.1126/scitranslmed.aaa5731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644635PMC
June 2015

I walk the line: how to tell MDS from other bone marrow failure conditions.

Curr Hematol Malig Rep 2014 Dec;9(4):389-99

Department of Oncology, Division of Hematological Malignancies, Johns Hopkins University, 1650 Orleans St, CRB1-290, Baltimore, MD, 21231, USA,

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by peripheral cytopenias and ineffective hematopoiesis. MDS is an example of an age-related malignancy and its increasing prevalence and incidence can be attributed to a greater life expectancy in developed countries. Although frequently encountered in hematology/oncology clinics, MDS may constitute a diagnostic challenge especially with equivocal bone marrow morphology. Certain syndromes of bone marrow failure (BMF) may mimic MDS and formulating a correct diagnosis is vital for adequate prognostication as well as therapeutic approaches. Metaphase karyotyping (MK) is a very important diagnostic tool and marker of prognosis and can be an indicator of response to certain therapies. Unfortunately, chromosomal abnormalities may only be found in approximately 50 % of patients with MDS. In this review, we discuss the diagnostic approaches to patients with pancytopenia with a particular focus on the growing number of somatic mutations through new molecular testing.
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http://dx.doi.org/10.1007/s11899-014-0224-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224968PMC
December 2014

Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited.

J Clin Oncol 2012 Apr 27;30(12):1343-9. Epub 2012 Feb 27.

Cleveland Clinic, Cleveland, OH, USA.

Purpose: Interstitial deletions of chromosome 5q are common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), pointing toward the pathogenic role of this region in disease phenotype and clonal evolution. The higher level of resolution of single-nucleotide polymorphism array (SNP-A) karyotyping may be used to find cryptic abnormalities and to precisely define the topographic features of the genomic lesions, allowing for more accurate clinical correlations.

Patients And Methods: We analyzed high-density SNP-A karyotyping at diagnosis for a cohort of 1,155 clinically well-annotated patients with malignant myeloid disorders. results: We identified chromosome 5q deletions in 142 (12%) of 1,155 patients and uniparental disomy segments (UPD) in four (0.35%) of 1,155 patients. Patients with deletions involving the centromeric and telomeric extremes of 5q have a more aggressive disease phenotype and additional chromosomal lesions. Lesions not involving the centromeric or telomeric extremes of 5q are not exclusive to 5q- syndrome but can be associated with other less aggressive forms of MDS. In addition, larger 5q deletions are associated with either del(17p) or UPD17p. In 31 of 33 patients with del(5q) AML, either a deletion involving the centromeric and/or telomeric regions or heterozygous mutations in NPM1 or MAML1 located in 5q35 were present.

Conclusion: Our results suggest that the extent of the affected region on 5q determines clinical characteristics that can be further modified by heterozygous mutations present in the telomeric extreme.
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http://dx.doi.org/10.1200/JCO.2011.36.1824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341146PMC
April 2012

Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies.

Blood 2011 Apr 1;117(17):4552-60. Epub 2011 Feb 1.

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute Center, Cleveland, OH, USA.

Single nucleotide polymorphism arrays (SNP-As) have emerged as an important tool in the identification of chromosomal defects undetected by metaphase cytogenetics (MC) in hematologic cancers, offering superior resolution of unbalanced chromosomal defects and acquired copy-neutral loss of heterozygosity. Myelodysplastic syndromes (MDSs) and related cancers share recurrent chromosomal defects and molecular lesions that predict outcomes. We hypothesized that combining SNP-A and MC could improve diagnosis/prognosis and further the molecular characterization of myeloid malignancies. We analyzed MC/SNP-A results from 430 patients (MDS = 250, MDS/myeloproliferative overlap neoplasm = 95, acute myeloid leukemia from MDS = 85). The frequency and clinical significance of genomic aberrations was compared between MC and MC plus SNP-A. Combined MC/SNP-A karyotyping lead to higher diagnostic yield of chromosomal defects (74% vs 44%, P < .0001), compared with MC alone, often through detection of novel lesions in patients with normal/noninformative (54%) and abnormal (62%) MC results. Newly detected SNP-A defects contributed to poorer prognosis for patients stratified by current morphologic and clinical risk schemes. The presence and number of new SNP-A detected lesions are independent predictors of overall and event-free survival. The significant diagnostic and prognostic contributions of SNP-A-detected defects in MDS and related diseases underscore the utility of SNP-A when combined with MC in hematologic malignancies.
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http://dx.doi.org/10.1182/blood-2010-07-295857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099573PMC
April 2011

Characterization of chromosome arm 20q abnormalities in myeloid malignancies using genome-wide single nucleotide polymorphism array analysis.

Genes Chromosomes Cancer 2010 Apr;49(4):390-9

Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Deletion of the long arm of chromosome 20 is a common abnormality associated with myeloid malignancies. We characterized abnormalities of chromosome 20 as defined by metaphase cytogenetics (MC) in patients with myeloid neoplasms to define commonly deleted regions (CDR) and commonly retained regions (CRR) using genome-wide, high resolution single nucleotide polymorphism array (SNP-A) analysis. We reviewed the MC results of a cohort of 1,162 patients with myeloid malignancies, including myelodysplastic syndromes (MDS), MDS/myeloproliferative neoplasia (MDS/MPN), and acute myeloid leukemia (AML). We further analyzed a subcohort of 532 patients by SNP-A using the Affymetrix Genome-Wide Human SNP Array 6.0 and GeneChip Human Mapping 250K Nsp arrays. By MC, 5% (54/1,162) harbored a deletion of 20q; in 30% (16/54), del(20q) was the sole cytogenetic abnormality. By SNP-A analysis, we identified del(20q) in 23 patients, 3 not detected by MC. In four cases, monosomy 20 with a marker chromosome by MC was proven to be an interstitial deletion of 20q by SNP-A. We defined 2 CDR and 2 CRR on chromosome arm 20q: CDR1 spanned 2.5 Mb between bands 20q11.23 and 20q12, while CDR2 encompassed 1.8 Mb within 20q13.12. CRR1 spanned 1.9 Mb within 20q11.21 and CRR2 encompassed 2.5 Mb within 20q13.33. In contrast to other chromosomes frequently affected by deletions, no somatic copy neutral loss of heterozygosity (CN-LOH) was detected. Our data suggest that SNP-A is useful for the detection of cryptic aberrations of chromosome 20q and allows for a more precise characterization of complex karyotypes. Furthermore, SNP-A allowed definition of a CDR on 20q.
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http://dx.doi.org/10.1002/gcc.20748DOI Listing
April 2010

Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies.

Cancer Res 2009 Nov 13;69(21):8482-90. Epub 2009 Oct 13.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Complete loss or deletion of the long arm of chromosome 5 is frequent in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The putative gene(s) deleted and responsible for the pathogenesis of these poor prognosis hematologic disorders remain controversial. This study is a comprehensive analysis of previously implicated and novel genes for epigenetic inactivation in AML and MDS. In 146 AML cases, methylation of CTNNA1 was frequent, and more common in AML patients with 5q deletion (31%) than those without 5q deletion (14%), whereas no methylation of other 5q genes was observed. In 31 MDS cases, CTNNA1 methylation was only found in high-risk MDS (>or=RAEB2), but not in low-risk MDS (
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http://dx.doi.org/10.1158/0008-5472.CAN-09-1153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081599PMC
November 2009

New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia.

J Clin Oncol 2009 Nov 21;27(31):5219-26. Epub 2009 Sep 21.

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Purpose: Cytogenetics is the primary outcome predictor in acute myeloid leukemia (AML). Metaphase cytogenetics (MC) detects an abnormal karyotype in only half of patients with AML, however. Single nucleotide polymorphism arrays (SNP-A) can detect acquired somatic uniparental disomy (UPD) and other cryptic defects, even in samples deemed normal by MC. We hypothesized that SNP-A will improve detection of chromosomal defects in AML and that this would enhance the prognostic value of MC.

Patients And Methods: We performed 250K and 6.0 SNP-A analyses on 140 patients with primary (p) and secondary (s) AML and correlated the results with clinical outcomes and Flt-3/nucleophosmin (NPM-1) status.

Results: SNP-A is more sensitive than MC in detecting unbalanced lesions (pAML, 65% v 39%, P = .002; and sAML, 78% v 51%, P = .003). Acquired somatic UPD, not detectable by MC, was common in our AML cohort (29% in pAML and 35% in sAML). Patients with SNP-A lesions including acquired somatic UPD exhibited worse overall survival (OS) and event-free survival (EFS) in pAML with normal MC and in pAML/sAML with abnormal MC. SNP-A improved the predictive value of Flt-3 internal tandem duplication/NPM-1 status, with inferior survival seen in patients with additional SNP-A defects. Multivariate analyses confirmed the independent predictive value of SNP-A defects for OS (hazard ratio [HR] = 2.52; 95% CI, 1.29 to 5.22; P = .006) and EFS (HR = 1.72; 95% CI, 1.12 to 3.48; P = .04).

Conclusion: SNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.
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http://dx.doi.org/10.1200/JCO.2009.21.9840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773477PMC
November 2009

FISH and SNP-A karyotyping in myelodysplastic syndromes: improving cytogenetic detection of del(5q), monosomy 7, del(7q), trisomy 8 and del(20q).

Leuk Res 2010 Apr 15;34(4):447-53. Epub 2009 Sep 15.

Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.

Cytogenetic aberrations identified by metaphase cytogenetics (MC) have important diagnostic, prognostic and therapeutic roles in myelodysplastic syndromes (MDS). Fluorescence in situ hybridization (FISH) complements MC by the ability to evaluate large numbers of both interphase and metaphase nuclei. However, clinically practical FISH strategies are limited to detection of known lesions. Single nucleotide polymorphism array (SNP-A)-based karyotyping can reveal unbalanced defects with superior resolution over MC and FISH and identify segmental uniparental disomy (UPD) undetectable by either method. Using a standardized approach, we focused our investigation on detection of -5/del(5q), -7/del(7q), trisomy 8 and del(20q) in patients with MDS (N=52), MDS/myeloproliferative overlap syndromes (N=7) and acute myeloid leukemia (N=15) using MC, FISH and SNP-A karyotyping. The detection rate for del(5q) was 30, 32 and 32% by MC, FISH, and SNP-A, respectively. No single method detected all defects, and detection rates improved when all methods were used. The rate for detection of del(5q) increased incrementally to 35% (MC+FISH), 38% (MC+SNP-A), 38% (FISH+SNP-A) and 39% (all three methods). Similar findings were observed for -7/del(7q), trisomy 8 and -20/del(20q). We conclude that MC, FISH and SNP-A are complementary techniques that, when applied and interpreted together, can improve the diagnostic yield for identifying genetic lesions in MDS and contribute to the better description of abnormal karyotypes.
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http://dx.doi.org/10.1016/j.leukres.2009.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826525PMC
April 2010

250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies.

Cancer Res 2008 Dec;68(24):10349-57

Department of Hematologic Oncology and Blood Disorders, Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio 44195, USA.

Two types of acquired loss of heterozygosity are possible in cancer: deletions and copy-neutral uniparental disomy (UPD). Conventionally, copy number losses are identified using metaphase cytogenetics, whereas detection of UPD is accomplished by microsatellite and copy number analysis and as such, is not often used clinically. Recently, introduction of single nucleotide polymorphism (SNP) microarrays has allowed for the systematic and sensitive detection of UPD in hematologic malignancies and other cancers. In this study, we have applied 250K SNP array technology to detect previously cryptic chromosomal changes, particularly UPD, in a cohort of 301 patients with myelodysplastic syndromes (MDS), overlap MDS/myeloproliferative disorders (MPD), MPD, and acute myeloid leukemia. We show that UPD is a common chromosomal defect in myeloid malignancies, particularly in chronic myelomonocytic leukemia (CMML; 48%) and MDS/MPD-unclassifiable (38%). Furthermore, we show that mapping minimally overlapping segmental UPD regions can help target the search for both known and unknown pathogenic mutations, including newly identified missense mutations in the proto-oncogene c-Cbl in 7 of 12 patients with UPD11q. Acquired mutations of c-Cbl E3 ubiquitin ligase may explain the pathogenesis of a clonal process in a subset of MDS/MPD, including CMML.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-2754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668538PMC
December 2008

Aberrant DNA methylation is a dominant mechanism in MDS progression to AML.

Blood 2009 Feb 2;113(6):1315-25. Epub 2008 Oct 2.

Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, OH 44195, USA.

Myelodysplastic syndromes (MDSs) are clonal hematologic disorders that frequently represent an intermediate disease stage before progression to acute myeloid leukemia (AML). As such, study of MDS/AML can provide insight into the mechanisms of neoplastic evolution. In 184 patients with MDS and AML, DNA methylation microarray and high-density single nucleotide polymorphism array (SNP-A) karyotyping were used to assess the relative contributions of aberrant DNA methylation and chromosomal deletions to tumor-suppressor gene (TSG) silencing during disease progression. Aberrant methylation was seen in every sample, on average affecting 91 of 1505 CpG loci in early MDS and 179 of 1505 loci after blast transformation (refractory anemia with excess blasts [RAEB]/AML). In contrast, chromosome aberrations were seen in 79% of early MDS samples and 90% of RAEB/AML samples, and were not as widely distributed over the genome. Analysis of the most frequently aberrantly methylated genes identified FZD9 as a candidate TSG on chromosome 7. In patients with chromosome deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome. These results indicate that aberrant methylation can cooperate with chromosome deletions to silence TSG. However, the ubiquity, extent, and correlation with disease progression suggest that aberrant DNA methylation is the dominant mechanism for TSG silencing and clonal variation in MDS evolution to AML.
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http://dx.doi.org/10.1182/blood-2008-06-163246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637194PMC
February 2009
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