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Research Roundup

Roundup for December 2021

The following is a high-level overview of medical papers and news articles, panned primarily for my own purposes to raise my level of knowledge and awareness of the current efforts in the fields of personal interest to me. This includes topics on conditions beyond HM's, such as solid cancers (for example prostate, breast, or colon), neurodegenerative conditions (such as Alzheimer's Disease), and of course technology (such as IT, Imaging, AI, and databases). Some of these I may later re-read to go a bit deeper regarding possible relevance or interest to CMPNRF.  But even with this preliminary coverage, it is difficult not to notice some important observations:

  • We are living in a very much connected and interconnected world where there are, or may very well be, relevance in the research of Hematologic Malignancies (HM's) to be found in other areas, if one only has an open mind to possibilities.

  • We are living in a world of incredible change and rapid pace of change; we only came to understand a year ago that there is such a concept as mRNA Vaccines for Covid, and just this month I read an article regarding a phase II study in a human, for an mRNA Vaccine for Cancer (colon cancer to be precise; by BioNTech). One year ago I did not have the foggiest idea what an mRNA was; this Christmas I received a gift of a book : "pigenetics, Nuclear Organization and Gene Function - with implications of epigenetic regulation and genetic architecture for human development and health  . . . who woulda thunk !

  • We are living in a world where one cannot work (including medical research) without the latest technology at our fingertips and the challenges to keeping up with the changes in that arena are formidable (as I know all too well, after only a few months after retiring from consulting in that field, I now feel very much "well past my best before date")

This list of papers is not in any sequence (but all published recently, this month of December 2021) and I make only the smallest of comments, but perhaps there may be some gems for those with a voracious appetite for reading such things. . . enjoy! 

Russ Hardy

[The roundup is prepared by Russ Hardy, Research Committee Member for the Canadian MPN Research Foundation. Russ' comments are provided in gray italics, and excerpts from the work are provided below each link in quotation marks.]

"When cancer cells communicate, numerous proteins constantly change how they interact with one another," says senior study author Chuan-Hsiang (Bear) Huang, M.D., Ph.D., assistant professor of pathology at the Johns Hopkins University School of Medicine. "Studying this signaling in depth and in real time has traditionally been difficult, so we needed a method that could simultaneously image, track and analyze everything happening in the network, and therefore, reveal the true relationships among these activities."

"The AI analysis enables us to read the barcodes in seconds rather than hours, a crucial step toward seeing how the activity of different proteins are synchronized over time," says Chi.

"Using biosensor barcodes, we hope to get more insights and more comprehensive views than ever before of how oncogenes [genes that initiate the development of cancer cells] affect communication among cancer cells, and with other networks such as those used by the immune system," says Huang. "These findings could help direct new interventions and treatments."

KAT6A and ENL form an epigenetic transcriptional control module to drive critical leukemogenic gene expression programs

Fangxue Yan, Jinyang Li, Jelena Milosevic, Ricardo Petroni, Suying Liu, Zhennan Shi, Salina Yuan, Janice M Reynaga, Yuwei Qi, Joshua Rico, Sixiang Yu, Yiman Liu, Susumu Rokudai, Neil Palmisiano, Sara E Meyer, Pamela J Sung, Liling Wan, Fei Lan, Benjamin A Garcia, Ben Z Stanger, David B Sykes and M. Andres Blanco, December 1, 2021 (Cancer Discovery, DOI: 10.1158/2159-8290.CD-20-1459)

"Abstract: Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene expression programs. We show that KAT6A is the initiator of a newly-described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyllysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small molecule inhibitors could be of high therapeutic interest for mono or combinatorial differentiation-based treatment of AML."

High-speed holography of cells spots physical beacons of disease, Duke University,  November 30, 2021, more information: Cindy X. Chen et al, Automated Classification of Breast Cancer Cells Using High-Throughput Holographic Cytometry, Frontiers in Physics (2021). DOI: 10.3389/fphy.2021.759142

This article was looking at unique methods to examine tissue samples; while the study dealt with breast cancer biopsy tissues, my question is could it be equally successful with bone marrow samples?

"Biomedical engineers at Duke University have engineered a holographic system capable of imaging and analyzing tens of thousands of cells per minute to both discover and recognize signs of disease. In the proof-of-concept demonstration, the technique distinguished between healthy samples and either cancerous or carcinogen-exposed, pre-cancerous cells with nearly 100% accuracy, using just four basic cellular physical parameters out of a holographic panel of 25. The results point toward a promising screening or diagnostic technology that is simpler and cheaper to use than current standard practices, making it a potential target for use in remote, low-resource settings. Holographic cytometry is an ultra-high throughput quantitative phase imaging modality that is capable of extracting subcellular information from millions of cells flowing through parallel microfluidic channels."

This paper covers some of the impacts on transcription factors and interactions with other chromatin partners that if interrupted lead to reduced immunity actors such as T-cells.

“Helios is one member of the Ikaros family of transcription factors, a set of proteins that play critical roles in the differentiation and regulation of hematopoietic cells including lymphocytes. Mutations in Ikaros family members are associated with both hematological cancers and inborn errors of immunity”

“Binding of Helios with specific partners mediates this regulation, which is ultimately necessary for the transcriptional programs that enable T cell homeostasis in health and disease.”

Researchers discover that proteasome molecules can join forces to prevent cancer, University of Montreal, November 30, 2021

(More information: Maxime Uriarte et al, Starvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis, Nature Communications (2021). DOI: 10.1038/s41467-021-27306-4)

This was a recent Canadian paper (yeah). UdeM-affiliated Maisonneuve-Rosemont Hospital Research Center. This is a very detailed and very technical paper, but may be of some interest to people in our group.

"El Bachir Affar's team looked at a tiny biological machine called the proteasome that exists in every cell in the body. This machine is responsible for breaking down and removing unwanted, malformed or excess proteins, a vital process for the proliferation and normal functioning of the cells. In addition, this process ensures the recycling of amino acids, which are the basic building blocks that the cells use to make new proteins.

"This discovery is very exciting," said Maisonneuve-Rosemont oncologist Dr. Pierre Dubé. "Dr. Affar and his team have discovered a new process that when faulty, can contribute to cancer. This opens the way to a new field of study and could lead to the identification of molecular targets for the treatment of cancers."

“Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus)”.

“Our data also suggest a link between SIPAN and tumor development/progression. First, certain cancer cells including T47D, PC3, MIA PaCa-2, have reduced ability to form SIPAN. Second, nutrient deprivation induces p53-dependent apoptosis with a notable upregulation of the p53 target gene NOXA; and inhibition of RAD23B and PSME3 prevents p53/NOXA upregulation and apoptosis. Third, we also found that oncogenic transformation of normal human fibroblasts results in reduced cell ability to form SIPAN and resistance to apoptosis induced by nutrient deprivation.”"

Changing the identity of cancer cells to eliminate them by University of Pennsylvania December 1, 2021 (study published in the journal Cancer  Discovery)

"The Study identifies an enzyme that regulates the process by which AML cells differentiate. In both cell lines and an animal model, the researchers found that inhibiting this enzyme, particularly in combination with other anti-cancer therapies, prompted AML cells to lose aspects of their identity associated with aggressive growth. The cells also began to exit the cell cycle, on the path toward maturing into a new cell type.

M. Andrés Blanco, an assistant professor at the University of Pennsylvania's lab is particularly interested in the epigenetic regulation of cell identity. One of the screened proteins that affected cell differentiation was KAT6A, an enzyme known as a histone acetyltransferase. As a histone acetyltransferase, KAT6A can add one of three different modifications to histones, proteins around which DNA winds. The finding helped the researchers understand that KAT6A is what's known as a "writer." It "writes" the modification of H3K9ac, and ENL is a "reader," taking in that modification and acting upon it."

"To an immunologist, autoimmune diseases like Type 1 diabetes are the polar opposite of cancer. In the former, the immune system goes into overdrive and attacks the body's own organs in a relentless manner, eventually causing disease; with cancer, the immune system shuts down and fails to mount an aggressive attack to stop cancer from forming.

In a new study by Yale Cancer Center, researchers show stem-like T cells within certain lymph nodes could be natural cancer fighters. Targeting these T cells—which are a type of white blood cells—with immunotherapy drugs could increase the number of cancer patients that respond to treatment."

"T cells in tumors become exhausted, but our study results show the stem-like T cells within the nearby lymph nodes do not experience exhaustion during the course of disease," said Kelli A. Connolly, a post-doctoral fellow at Yale Cancer Center and lead author of the study. "This could be an important treatment advance as the potential to respond to immunotherapy is preserved."

The above study was performed relating to solid tumor (specifically Non–small cell lung cancer (NSCLC))  . . . not being familiar with immunotherapies for HM’s, I was just wondering if there were similar immune responses and studies for HMs.

Researchers discover that proteasome molecules can join forces to prevent cancer, University of Montreal, November 30, 2021

(More information: Maxime Uriarte et al, Starvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis, Nature Communications (2021). DOI: 10.1038/s41467-021-27306-4)

This was a recent Canadian paper (yeah). UdeM-affiliated Maisonneuve-Rosemont Hospital Research Center. This is a very detailed and very technical paper, but may be of some interest to people in our group.

"El Bachir Affar's team looked at a tiny biological machine called the proteasome that exists in every cell in the body. This machine is responsible for breaking down and removing unwanted, malformed or excess proteins, a vital process for the proliferation and normal functioning of the cells. In addition, this process ensures the recycling of amino acids, which are the basic building blocks that the cells use to make new proteins.

"This discovery is very exciting," said Maisonneuve-Rosemont oncologist Dr. Pierre Dubé. "Dr. Affar and his team have discovered a new process that when faulty, can contribute to cancer. This opens the way to a new field of study and could lead to the identification of molecular targets for the treatment of cancers."

“Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus)”.

“Our data also suggest a link between SIPAN and tumor development/progression. First, certain cancer cells including T47D, PC3, MIA PaCa-2, have reduced ability to form SIPAN. Second, nutrient deprivation induces p53-dependent apoptosis with a notable upregulation of the p53 target gene NOXA; and inhibition of RAD23B and PSME3 prevents p53/NOXA upregulation and apoptosis. Third, we also found that oncogenic transformation of normal human fibroblasts results in reduced cell ability to form SIPAN and resistance to apoptosis induced by nutrient deprivation.”"

Stochastic chromatin packing of 3D mitotic chromosomes revealed by coherent X-rays, Daeho Sung, Chan Lim,  Masatoshi Takagi, Chulho Jung, Heemin Lee,  Do Hyung Cho, J et al

PNAS November 16, 2021.

This paper combines molecular biology with technology to image structures and provide insight as to how architecture impacts functions.

“The structural link between meter-long DNA molecules and chromosomes a few microns in size and their highly space-effective and fault-free packing and unpacking mechanisms remain a puzzle. This research addressed this fundamental issue by resolving a three-dimensional (3D) structure of human chromosomes using cryogenic coherent X-ray diffraction tomography.

While supporting the structural analysis, molecular dynamics simulations further elucidate the critical role of short-range attraction between chromatins and DNA-binding proteins in forming micrometer-sized chromosomes.”

Researchers discover that proteasome molecules can join forces to prevent cancer, University of Montreal, November 30, 2021

(More information: Maxime Uriarte et al, Starvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis, Nature Communications (2021). DOI: 10.1038/s41467-021-27306-4)

This was a recent Canadian paper (yeah). UdeM-affiliated Maisonneuve-Rosemont Hospital Research Center. This is a very detailed and very technical paper, but may be of some interest to people in our group.

"El Bachir Affar's team looked at a tiny biological machine called the proteasome that exists in every cell in the body. This machine is responsible for breaking down and removing unwanted, malformed or excess proteins, a vital process for the proliferation and normal functioning of the cells. In addition, this process ensures the recycling of amino acids, which are the basic building blocks that the cells use to make new proteins.

"This discovery is very exciting," said Maisonneuve-Rosemont oncologist Dr. Pierre Dubé. "Dr. Affar and his team have discovered a new process that when faulty, can contribute to cancer. This opens the way to a new field of study and could lead to the identification of molecular targets for the treatment of cancers."

“Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus)”.

“Our data also suggest a link between SIPAN and tumor development/progression. First, certain cancer cells including T47D, PC3, MIA PaCa-2, have reduced ability to form SIPAN. Second, nutrient deprivation induces p53-dependent apoptosis with a notable upregulation of the p53 target gene NOXA; and inhibition of RAD23B and PSME3 prevents p53/NOXA upregulation and apoptosis. Third, we also found that oncogenic transformation of normal human fibroblasts results in reduced cell ability to form SIPAN and resistance to apoptosis induced by nutrient deprivation.”"

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More December Roundup items coming soon!

 I found this line of research (looking at some of the features of the Interactome, particularly related to cell differentiation processes) to be an interesting approach with perhaps some future applications to clinical treatments. The study was focused on AML, but perhaps may also be relevant to other HM’s?”

This paper discusses the use of labelled peptides for imaging and probing radiotheranostics.

68Ga- and 211At-Labeled RGD Peptides for Radiotheranostics with Multiradionuclides

Kazuma Ogawa*, Hiroaki Echigo, Kenji Mishiro, Saki Hirata, Kohshin Washiyama, Yoji Kitamura, Kazuhiro Takahashi, Kazuhiro Shiba, and Seigo Kinuya  Molecular Pharmaceutics 2021, 18, 9,

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.1c00460

 

“In this study, we hypothesized that probes for radiotheranostics combined with multiradionuclides, such as 68Ga and 211At, have useful clinical applications. These results indicate the usefulness of these probes in radiotheranostics with multiradionuclides, such as a radiometal and a radiohalogen, and they could contribute to a personalized medicine regimen.”

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