The Impact of PI3-kinase/RAS Pathway Cooperating Mutations in the Evolution of KMT2A-rearranged Leukemia

Abstract Abstract Introduction: With the development of next generation sequencing (NGS), the interrelation between genetic and epigenetic abnormality in myeloid malignancies has attracted significant attention. Clinical reports provide strong evidence that while the specific gene mutations are the initial event for the myeloid malignancies, the concomitant gene mutations contribute to the disease progression. Although ASXL1 mutations have been found in myeloid malignancies, the impact of co-mutation with ASXL1 on the disease progression remains largely unknown. In the current study, we aim to investigate the clinical significance of the association between ASXL1 mutations and a spectrum of gene mutations in a large cohort of patients with myeloid malignancies. Methods: Targeted sequencing including 112 hematopoietic malignancy-related genes was used to analyze the gene mutations in patients with ASXL1 mutations. The impact of gene mutations on clinical characteristics and prognosis was further analyzed. The correlation between clinical/laboratory features and the gene mutations was performed by the χ2 test, and differences in values and in ranks were assessed by Student t-tests. Overall survival rate was assessed by the Kaplan-Meier method and calculated by the Log-rank test. Results: A cohort of 138 myeloid malignant patients harboring ASXL1 mutations was recruited to the current study, including patients with myelodysplastic syndromes (MDS) (37.68%, n = 52), myeloproliferative neoplasms (MPN) (21.01%, n = 29), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (7.25%, n = 10), and acute myeloid leukemia (AML) (34.06%, n = 47). In addition, to ASXL1 mutations, 89 genes were mutated in these patients, and 96.4% (133) of the patients were accompanied by at least one gene mutation. Among those mutated genes, 55.8% (77/138) was epigenetic genes, 65.9% (91/138) was signal transduction pathway genes, 28.2% (39/138) was spliceosome related genes, 36.9% (51/138) was transcription factor genes, and 18.8% (26/138) was cell cycle and apoptosis related genes. The most common co-mutated genes were RAS pathway related genes (25.4%, 35/138) and SETBP1 (21.7%, 30/138). Patients with ASXL1 and RAS pathway co-mutations (ASXL1mutRASmut) had significantly lower levels of hemoglobin and platelets compared to ASXL1 mutated patients without RAS pathway mutation (ASXL1mutRASwt) (hemoglobin 81 (33-152) g/L vs. 96 (18-195) g/L, P=0.012; and platelets (51 (8-695)×109/L vs. 75 (3-3149) × 109/L, P=0.032, respectively). Importantly, MDS patients with ASXL1mutRASmut were more likely to be associated with high International Prognostic Scoring System (IPSS) scores (P=0.016). Moreover, the median survival time of these ASXL1mutRASmut patients (mean = 17 months, 1-35 months) was significantly shorter than that of ASXL1mutRASwtpatients (mean = 21 months, 2-75 months) (P=0.031). Conclusions: Our study provides a comprehensive overview of the association between the clinical features and prognosis with genes co-mutated with ASXL1 in patients with myeloid malignancies. We conclude that concomitant mutations of ASXL1 with RAS pathway genes associate with high risk of myeloid transformation and lower overall survival rates. Disclosures No relevant conflicts of interest to declare.

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A phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.274 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 274-274 ◽

Cited By ~ 7

Author(s):

Akash Patnaik ◽

Justin Kung ◽

Massimo Loda ◽

Mary-Ellen Taplin ◽

Rosina Lis ◽

...

Keyword(s):

Prostate Cancer ◽

Lymph Node ◽

Combination Therapy ◽

Metastatic Prostate Cancer ◽

Single Agent ◽

Pi3 Kinase ◽

Primary Study ◽

Pi3k Activation ◽

Castrate Resistant ◽

The Impact

274 Background: There is cross-talk between PI3-kinase (PI3K) pathway and androgen receptor (AR) signaling pathways, respectively, which are both critical for cell survival in castrate-resistant prostate cancer (CRPC). The primary study objective is to determine the safety profile and MTD of BKM120 (B, pan-PI3K inhibitor) in combination with abiraterone/prednisone (A/P) in CRPC patients. The secondary objectives are to assess the impact of PTEN status on duration of response/time to progression in the expansion cohort, and to evaluate the impact of B on a PI3-kinase activation fingerprint in metastatic bone or lymph node tissue samples. An exploratory objective is to assess the effect of B on transcription of a set of AR-regulated genes in metastatic bone biopsy samples. Methods: The trial design involves a 14 day lead-in phase with B alone, to assess single-agent toxicity and perform correlative studies. A/P is combined with B at the end of 14 days using the standard 3+3 dose-escalation design with 3 dose levels of B, and participants are assessed for safety and MTD on the combination therapy. To determine PD impact of single agent B on the PI3K activation signature at a metastatic site, a mandatory CT-guided bone or lymph node biopsy is performed prior to B initiation and at the end of 2 weeks on B single-agent therapy. Immunohistochemical (IHC) stains for three markers (p-AKT, p-S6 and PTEN) are used to obtain a semi-quantitative PI3K activation score, based on the quartile levels of continuous staining scores of each marker. Results: Patient 1 had symptomatic bone pain improvement, marked decline in narcotic pain requirements and a biochemical decline in PSA from 156.5 to a PSA nadir of 9.2 within 4 weeks of combination therapy. Patient 3 had a symptomatic and >90% biochemical improvement and has currently completed 15 cycles on treatment, and remains on study to date. RT-PCR analysis showed that the feedback circuitry between PI3K and AR signaling is heterogeneous in the metastatic prostate cancer-bone microenvironment, and dependent on tumor PTEN status. Conclusions: Preliminary data shows promising anti-tumor activity in CRPC patients from dual targeting of PI3K and AR pathways with B and A/P, respectively. Clinical trial information: NCT01741753.

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Formation of Lunar Craters and Bright Rays as a Result of Meteorite Impacts

Symposium - International Astronomical Union ◽

10.1017/s0074180900178404 ◽

1962 ◽

Vol 14 ◽

pp. 415-418

Author(s):

K. P. Stanyukovich ◽

V. A. Bronshten

Keyword(s):

Explosive Charge ◽

The Moon ◽

Meteorite Impacts ◽

The Earth ◽

Lunar Craters ◽

The Impact

The phenomena accompanying the impact of large meteorites on the surface of the Moon or of the Earth can be examined on the basis of the theory of explosive phenomena if we assume that, instead of an exploding meteorite moving inside the rock, we have an explosive charge (equivalent in energy), situated at a certain distance under the surface.

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The Geosciences Applied to Lunar Exploration

Symposium - International Astronomical Union ◽

10.1017/s0074180900178222 ◽

1962 ◽

Vol 14 ◽

pp. 169-257 ◽

Cited By ~ 9

Author(s):

J. Green

Keyword(s):

Lunar Surface ◽

Probable Mechanism ◽

Point Of View ◽

Lunar Exploration ◽

Geological Model ◽

Apply Geophysics ◽

Surface Features ◽

The Impact

The term geo-sciences has been used here to include the disciplines geology, geophysics and geochemistry. However, in order to apply geophysics and geochemistry effectively one must begin with a geological model. Therefore, the science of geology should be used as the basis for lunar exploration. From an astronomical point of view, a lunar terrain heavily impacted with meteors appears the more reasonable; although from a geological standpoint, volcanism seems the more probable mechanism. A surface liberally marked with volcanic features has been advocated by such geologists as Bülow, Dana, Suess, von Wolff, Shaler, Spurr, and Kuno. In this paper, both the impact and volcanic hypotheses are considered in the application of the geo-sciences to manned lunar exploration. However, more emphasis is placed on the volcanic, or more correctly the defluidization, hypothesis to account for lunar surface features.

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Asteroid and Comet Impact Speeds upon Mars: Significance for Panspermia and the Supply of Organics

International Astronomical Union Colloquium ◽

10.1017/s0252921100014718 ◽

1997 ◽

Vol 161 ◽

pp. 197-201 ◽

Cited By ~ 1

Author(s):

Duncan Steel

Keyword(s):

Probability Distributions ◽

Regions Of Interest ◽

Significant Fraction ◽

Organic Chemicals ◽

Impact Speed ◽

The Mean ◽

The Impact

AbstractWhilst lithopanspermia depends upon massive impacts occurring at a speed above some limit, the intact delivery of organic chemicals or other volatiles to a planet requires the impact speed to be below some other limit such that a significant fraction of that material escapes destruction. Thus the two opposite ends of the impact speed distributions are the regions of interest in the bioastronomical context, whereas much modelling work on impacts delivers, or makes use of, only the mean speed. Here the probability distributions of impact speeds upon Mars are calculated for (i) the orbital distribution of known asteroids; and (ii) the expected distribution of near-parabolic cometary orbits. It is found that cometary impacts are far more likely to eject rocks from Mars (over 99 percent of the cometary impacts are at speeds above 20 km/sec, but at most 5 percent of the asteroidal impacts); paradoxically, the objects impacting at speeds low enough to make organic/volatile survival possible (the asteroids) are those which are depleted in such species.

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Organic Syntheses During the Impact of a Comet with a Gaseous Planet

International Astronomical Union Colloquium ◽

10.1017/s0252921100014706 ◽

1997 ◽

Vol 161 ◽

pp. 189-195

Author(s):

Cesare Guaita ◽

Roberto Crippa ◽

Federico Manzini

Keyword(s):

Polymeric Material ◽

Molecular Form ◽

Parent Compound ◽

Blue Filter ◽

Organic Syntheses ◽

The Impact

AbstractA large amount of CO has been detected above many SL9/Jupiter impacts. This gas was never detected before the collision. So, in our opinion, CO was released from a parent compound during the collision. We identify this compound as POM (polyoxymethylene), a formaldehyde (HCHO) polymer that, when suddenly heated, reformes monomeric HCHO. At temperatures higher than 1200°K HCHO cannot exist in molecular form and the most probable result of its decomposition is the formation of CO. At lower temperatures, HCHO can react with NH3 and/or HCN to form high UV-absorbing polymeric material. In our opinion, this kind of material has also to be taken in to account to explain the complex evolution of some SL9 impacts that we observed in CCD images taken with a blue filter.

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Hydrogen Cyanide Polymers from the Impact of Comet P/Shoemaker-Levy 9 on Jupiter

International Astronomical Union Colloquium ◽

10.1017/s025292110001469x ◽

1997 ◽

Vol 161 ◽

pp. 179-187

Author(s):

Clifford N. Matthews ◽

Rose A. Pesce-Rodriguez ◽

Shirley A. Liebman

Keyword(s):

Amino Acids ◽

Solar System ◽

Hydrogen Cyanide ◽

Nitrogen Heterocycles ◽

Laboratory Studies ◽

Heterogeneous Solids ◽

The Many ◽

Comet Halley ◽

The Impact ◽

By Products

AbstractHydrogen cyanide polymers – heterogeneous solids ranging in color from yellow to orange to brown to black – may be among the organic macromolecules most readily formed within the Solar System. The non-volatile black crust of comet Halley, for example, as well as the extensive orangebrown streaks in the atmosphere of Jupiter, might consist largely of such polymers synthesized from HCN formed by photolysis of methane and ammonia, the color observed depending on the concentration of HCN involved. Laboratory studies of these ubiquitous compounds point to the presence of polyamidine structures synthesized directly from hydrogen cyanide. These would be converted by water to polypeptides which can be further hydrolyzed to α-amino acids. Black polymers and multimers with conjugated ladder structures derived from HCN could also be formed and might well be the source of the many nitrogen heterocycles, adenine included, observed after pyrolysis. The dark brown color arising from the impacts of comet P/Shoemaker-Levy 9 on Jupiter might therefore be mainly caused by the presence of HCN polymers, whether originally present, deposited by the impactor or synthesized directly from HCN. Spectroscopic detection of these predicted macromolecules and their hydrolytic and pyrolytic by-products would strengthen significantly the hypothesis that cyanide polymerization is a preferred pathway for prebiotic and extraterrestrial chemistry.

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Unusual Microstructure in Shock-Compacted Graphite

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100069363 ◽

1970 ◽

Vol 28 ◽

pp. 474-475

Author(s):

Lucien F. Trueb

Keyword(s):

Mechanical Characteristic ◽

Compression Wave ◽

Gray Zone ◽

Flyer Plate ◽

Compacted Graphite ◽

The Impact

Crushed and statically compressed Madagascar graphite that was explosively shocked at 425 kb by means of a planar flyer-plate is characterized by a black zone extending for 2 to 3 nun below the impact plane of the driver. Beyond this point, the material assumes the normal gray color of graphite. The thickness of the black zone is identical with the distance taken by the relaxation wave to overtake the compression wave.The main mechanical characteristic of the black material is its great hardness; steel scalpels and razor blades are readily blunted during attempts to cut it. An average microhardness value of 95-3 DPHN was obtained with a 10 kg load. This figure is a minimum because the indentations were usually cracked; 14.8 DPHN was measured in the gray zone.

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Drug Induced Changes in Cell Organelles

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100100299 ◽

1968 ◽

Vol 26 ◽

pp. 110-111

Author(s):

Sarah A. Luse

Keyword(s):

Clinical Medicine ◽

Cell Organelles ◽

Riboflavin Deficiency ◽

Drug Induced ◽

New Era ◽

Health And Disease ◽

In The Beginning ◽

Cellular Pathology ◽

Induced Changes ◽

The Impact

In the mid-nineteenth century Virchow revolutionized pathology by introduction of the concept of “cellular pathology”. Today, a century later, this term has increasing significance in health and disease. We now are in the beginning of a new era in pathology, one which might well be termed “organelle pathology” or “subcellular pathology”. The impact of lysosomal diseases on clinical medicine exemplifies this role of pathology of organelles in elucidation of disease today.Another aspect of cell organelles of prime importance is their pathologic alteration by drugs, toxins, hormones and malnutrition. The sensitivity of cell organelles to minute alterations in their environment offers an accurate evaluation of the site of action of drugs in the study of both function and toxicity. Examples of mitochondrial lesions include the effect of DDD on the adrenal cortex, riboflavin deficiency on liver cells, elevated blood ammonia on the neuron and some 8-aminoquinolines on myocardium.

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Fluorescent potentiometric dyes for membrane-potential imaging

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100168566 ◽

1994 ◽

Vol 52 ◽

pp. 166-167

Author(s):

Leslie M. Loew

Keyword(s):

Membrane Potential ◽

Single Cells ◽

Quantitative Imaging ◽

Optical Recording ◽

Biological Processes ◽

Major Focus ◽

The Past ◽

Excitable Systems ◽

Major Application ◽

The Impact

A major application of potentiometric dyes has been the multisite optical recording of electrical activity in excitable systems. After being championed by L.B. Cohen and his colleagues for the past 20 years, the impact of this technology is rapidly being felt and is spreading to an increasing number of neuroscience laboratories. A second class of experiments involves using dyes to image membrane potential distributions in single cells by digital imaging microscopy - a major focus of this lab. These studies usually do not require the temporal resolution of multisite optical recording, being primarily focussed on slow cell biological processes, and therefore can achieve much higher spatial resolution. We have developed 2 methods for quantitative imaging of membrane potential. One method uses dual wavelength imaging of membrane-staining dyes and the other uses quantitative 3D imaging of a fluorescent lipophilic cation; the dyes used in each case were synthesized for this purpose in this laboratory.

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