NKL-Code in Normal and Aberrant Hematopoiesis

We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes, these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, the aberrant overexpression of NKL-code-members or the ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, I provide an overview of the NKL-code in normal hematopoiesis and instance mechanisms of deregulation and oncogenic functions of selected NKL genes in hematologic cancers. As well as published clinical studies, our conclusions are based on experimental work using hematopoietic cell lines which represent useful models to characterize the role of NKL homeobox genes in specific tumor types.

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The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer

Biomedicines ◽

10.3390/biomedicines9080921 ◽

2021 ◽

Vol 9 (8) ◽

pp. 921

Author(s):

Ekaterina Mikhailovna Stasevich ◽

Matvey Mikhailovich Murashko ◽

Lyudmila Sergeevna Zinevich ◽

Denis Eriksonovich Demin ◽

Anton Markovich Schwartz

Keyword(s):

Malignant Tumors ◽

Current Data ◽

Cellular Processes ◽

Cell Divisions ◽

Specific Tumor ◽

Different Types ◽

Myc Gene ◽

Non Coding Rnas ◽

Tumor Types

Alterations in the expression level of the MYC gene are often found in the cells of various malignant tumors. Overexpressed MYC has been shown to stimulate the main processes of oncogenesis: uncontrolled growth, unlimited cell divisions, avoidance of apoptosis and immune response, changes in cellular metabolism, genomic instability, metastasis, and angiogenesis. Thus, controlling the expression of MYC is considered as an approach for targeted cancer treatment. Since c-Myc is also a crucial regulator of many cellular processes in healthy cells, it is necessary to find ways for selective regulation of MYC expression in tumor cells. Many recent studies have demonstrated that non-coding RNAs play an important role in the regulation of the transcription and translation of this gene and some RNAs directly interact with the c-Myc protein, affecting its stability. In this review, we summarize current data on the regulation of MYC by various non-coding RNAs that can potentially be targeted in specific tumor types.

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ROLE OF ACCESS OSTEOTOMY IN HEAD AND NECK LESIONS – A REVIEW

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2022.v15i1.43312 ◽

2021 ◽

pp. 25-30

Author(s):

BHARATHI K ◽

MANOJ CHANDRASEKAR ◽

KAPIL DEV KUMAR S ◽

BALA JAGANNATH GUPTA B

Keyword(s):

Head And Neck ◽

Surgical Resection ◽

Hand Search ◽

Surgical Access ◽

Operative Care ◽

Specific Tumor ◽

Surgical Field ◽

Tumor Types ◽

Neurovascular Structures

The surgical resection of the head and neck lesions summarizes the principles, classifications, applications, complications, and post-operative care of osteotomy with the standard protocols performed safely. It often poses a great surgical challenge due to the anatomical complexity, difficulty in accessibility, and proximity of vital structures. A multidisciplinary approach is often required in these situations for their better exposure to provide surgical access. Access osteotomy is the choice and type for these head and neck lesions, which are most often based on the anatomic extent of the lesion, vascularity of the lesion, and involvement of neurovascular structures in and around it. The literature search using Medline from the year 1986 to 2019 were performed and textbooks were also collected by hand search from the same period. The role of aggressive surgical resection has not been established for malignant head and neck lesions with the technical feasibility and its efficacy for specific tumor types must be defined by the future studies. Thus, we would like to conclude that access osteotomy allows the surgeon a better view and an access of the surgical field to resect the tumor completely with safer margins, preserving the vital structures, pre-operative functions, and reducing post-operative complications.

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Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

Cancers ◽

10.3390/cancers14010245 ◽

2022 ◽

Vol 14 (1) ◽

pp. 245

Author(s):

Ruggiero Gorgoglione ◽

Valeria Impedovo ◽

Christopher L. Riley ◽

Deborah Fratantonio ◽

Stefano Tiziani ◽

...

Keyword(s):

Uncoupling Protein ◽

Cell Metabolism ◽

Redox Homeostasis ◽

Nucleotide Biosynthesis ◽

Specific Tumor ◽

Mitochondrial Carrier Family ◽

Cancer Types ◽

Cancer Cell Metabolism ◽

Tumor Types

Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.

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Erythroid-restricted expression of homeobox genes of the human HOX 2 locus

Blood ◽

10.1182/blood.v78.9.2248.bloodjournal7892248 ◽

1991 ◽

Vol 78 (9) ◽

pp. 2248-2252 ◽

Cited By ~ 1

Author(s):

CH Mathews ◽

K Detmer ◽

E Boncinelli ◽

HJ Lawrence ◽

C Largman

Keyword(s):

Cell Lines ◽

Expression Patterns ◽

Homeobox Genes ◽

Homeobox Gene ◽

Leukemic Cell ◽

Hematopoietic Cell ◽

Erythroid Cell ◽

Small Series ◽

Hematopoietic Cell Lines ◽

In Cells

We have previously reported that certain members of the HOX 1 and HOX 2 clusters of class 1 homeobox-containing genes showed lineage-restricted patterns of expression in a small series of human hematopoietic cell lines. We now report on the expression patterns of the entire HOX 2 cluster, consisting of nine homeobox genes, in a broad survey of leukemic cell lines of different phenotypes. The most striking observation is that all but one of the HOX 2 genes are consistently expressed in cells with erythroid character and/or potential, but, with rare exception, not in cells with myelomonocytic or T- or B-lymphoid phenotype. By contrast, several genes of the HOX 1 and 3 loci are not expressed in erythroid lines. Within erythroid cell lines, many of the HOX 2 genes are expressed as multiple transcripts. Expression of some HOX 2 genes is detectable in normal human marrow. These data show that in human hematopoietic cell lines HOX 2 homeobox gene expression is largely restricted to cells of erythroid phenotype and suggest that these genes play a role in erythropoiesis.

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Loss of Rb1 in the gastrointestinal tract of Apc1638N mice promotes tumors of the cecum and proximal colon

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0802933105 ◽

2008 ◽

Vol 105 (40) ◽

pp. 15493-15498 ◽

Cited By ~ 15

Author(s):

Melanie H. Kucherlapati ◽

Kan Yang ◽

Kunhua Fan ◽

Mari Kuraguchi ◽

Dmitriy Sonkin ◽

...

Keyword(s):

Small Intestine ◽

Profile Analysis ◽

Expression Profiles ◽

Expression Patterns ◽

Tumor Location ◽

Proximal Colon ◽

Gi Tract ◽

Expression Profile Analysis ◽

Tumor Types

To examine the role of Rb1 in gastrointestinal (GI) tumors, we generated mice with an Apc1638N allele, Rbtm2brn floxed alleles, and a villin-cre transgene (RBVCA). These animals had exon 19 deleted from Rb1 throughout the GI tract. We have shown previously that Rb1 deficiency is insufficient for GI tumor initiation, with inactivation of an Apc allele capable of overcoming the insufficiency. In this study we demonstrate that RBVCA mice have reduced median survival because of an increase in tumor incidence and multiplicity in the cecum and the proximal colon. Large intestinal tumors are predominantly adenomas, whereas the tumors of the small intestine are a mixture of adenomas and adenocarcinomas. We find truncation mutations to the second Apc allele in tumors of both the large and small intestine. Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. Substantial expression patterns compare to human colorectal cancer, including recapitulation of embryonic genes. Our results indicate that Rb1 has significant influence over tumor location in the GI tract, and that both cecal and duodenal tumors initiate through inactivation of Apc. Expression profile analysis indicates the two tumor types differentially regulate distinct sets of genes that are over-expressed in a majority of human colorectal carcinomas.

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Targeting MCL-1 in cancer: current status and perspectives

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01079-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Haolan Wang ◽

Ming Guo ◽

Hudie Wei ◽

Yongheng Chen

Keyword(s):

Clinical Trials ◽

Cancer Therapy ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Current Status ◽

Significant Progress ◽

Apoptotic Pathway ◽

Antiapoptotic Protein ◽

Tumor Types

AbstractMyeloid leukemia 1 (MCL-1) is an antiapoptotic protein of the BCL-2 family that prevents apoptosis by binding to the pro-apoptotic BCL-2 proteins. Overexpression of MCL-1 is frequently observed in many tumor types and is closely associated with tumorigenesis, poor prognosis and drug resistance. The central role of MCL-1 in regulating the mitochondrial apoptotic pathway makes it an attractive target for cancer therapy. Significant progress has been made with regard to MCL-1 inhibitors, some of which have entered clinical trials. Here, we discuss the mechanism by which MCL-1 regulates cancer cell apoptosis and review the progress related to MCL-1 small molecule inhibitors and their role in cancer therapy.

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Retinoids in haematology : a timely revival?

Blood ◽

10.1182/blood.2020010100 ◽

2021 ◽

Author(s):

Hugues de The ◽

Cécile Esnault ◽

Marie-Claude Geoffroy

Keyword(s):

Nuclear Receptors ◽

Myeloid Leukemia ◽

Promyelocytic Leukemia ◽

Retinoic Acid Receptors ◽

Hematopoietic Differentiation ◽

Retinoid Signaling ◽

Master Genes ◽

Significant Interest ◽

Rare Malignancy

The retinoic acid receptors (RARA, RARB, RARG) are ligand-regulated nuclear receptors which act as transcriptional switches. These master genes drew significant interest in the 1990s due to their key roles in embryogenesis and involvement in a rare malignancy, acute promyelocytic leukemia (APL), in which the RARA (and very rarely RARG or RARB) genes are rearranged, underscoring the central role of deregulated retinoid signaling in leukemogenesis. A number of recent provocative observations have revived interest in the roles of retinoids in non-APL acute myeloid leukemia (AMLs), as well as in normal hematopoietic differentiation. Here we review the role of retinoids in hematopoiesis, as well as in the treatment of non-APL AMLs. From this perspective, broader uses of retinoids in the management of hematopoietic tumors is discussed.

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Erythroid-restricted expression of homeobox genes of the human HOX 2 locus

Blood ◽

10.1182/blood.v78.9.2248.2248 ◽

1991 ◽

Vol 78 (9) ◽

pp. 2248-2252 ◽

Cited By ~ 28

Author(s):

CH Mathews ◽

K Detmer ◽

E Boncinelli ◽

HJ Lawrence ◽

C Largman

Keyword(s):

Cell Lines ◽

Expression Patterns ◽

Homeobox Genes ◽

Homeobox Gene ◽

Leukemic Cell ◽

Hematopoietic Cell ◽

Erythroid Cell ◽

Small Series ◽

Hematopoietic Cell Lines ◽

In Cells

Abstract We have previously reported that certain members of the HOX 1 and HOX 2 clusters of class 1 homeobox-containing genes showed lineage-restricted patterns of expression in a small series of human hematopoietic cell lines. We now report on the expression patterns of the entire HOX 2 cluster, consisting of nine homeobox genes, in a broad survey of leukemic cell lines of different phenotypes. The most striking observation is that all but one of the HOX 2 genes are consistently expressed in cells with erythroid character and/or potential, but, with rare exception, not in cells with myelomonocytic or T- or B-lymphoid phenotype. By contrast, several genes of the HOX 1 and 3 loci are not expressed in erythroid lines. Within erythroid cell lines, many of the HOX 2 genes are expressed as multiple transcripts. Expression of some HOX 2 genes is detectable in normal human marrow. These data show that in human hematopoietic cell lines HOX 2 homeobox gene expression is largely restricted to cells of erythroid phenotype and suggest that these genes play a role in erythropoiesis.

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The role of TGF-β pathway in immune regulation as a potential biomarker of immunotherapy across pan-cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15187 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15187-e15187

Author(s):

Yongmei Yin ◽

Yan Liang ◽

Zhengyi Zhao ◽

Yuzi Zhang ◽

Jing Zhao ◽

...

Keyword(s):

Overall Survival ◽

Immune Regulation ◽

Transforming Growth Factor ◽

Expression Patterns ◽

Group Versus ◽

Chinese Patients ◽

Wild Type ◽

Potential Biomarker ◽

Tumor Types

e15187 Background: The transforming growth factor beta (TGF-β) signaling pathway has been reported to be involved in both tumor suppression and tumor promotion. However, the role of TGF-β pathway in immune regulation for cancer patients and its influences on immunotherapy efficacy have not been systematically investigated. Methods: Available data of whole-exome sequencing, mRNA expression, baseline characterization and prognosis information of 10,912 pancancer patients were adopted from The Cancer Genome Altas (TCGA) to explore the role of TGF-β pathway in immune regulation. Formalin-fixed, paraffin-embedded tissue samples from 6,717 Chinese patients with over 17 tumor types were assayed by next-generation sequencing with a panel with 381 cancer related genes as a validation cohort (3DMed cohort). Datasets from the public MSK cohort (N = 1,610) was used to explore the association of TGF-β pathway in patient survival. Results: The highest prevalence of single nucleotide variation (SNVs) in TGF-β pathway fell in digestive system tumors in both TCGA and 3DMed cohorts, including colon adenocarcinoma pancreatic adenocarcinoma, rectum adenocarcinoma, and stomach adenocarcinoma. TGF-β pathway SNVs was significantly correlated with high microsatellite instability, high tumor mutational burden (TMB-H) status and high neoantigen burden (TNB-H) ( p< 0.001) across all tumor types. Notably, the correlation of pathway alternation and TMB or TNB remained significance in microsatellite stable patients ( p< 0.001). Alternations of the pathway genes were associated with significant different expression patterns of immune-related genes such as the up-regulation of CD28, CD40, and CCL5, etc. Consistently, significant higher levels of CD8 ( p< 0.001), dendritic cells ( p< 0.001), and neutrophil cells ( p< 0.001) were observed in the pathway mutated samples. Patients with TGF-β pathway mutations exhibited significant worse prognosis than the wild-type patients regardless of interventions (overall survival, HR 1.20, 95% CI 1.08-1.33; p= 0.001). However, when treated with immune checkpoint inhibitors, superior survival benefit was observed in patients in the mutation group versus the wild-type group (overall survival, HR 0.73, 95% CI 0.61-0.88; p= 0.001). Conclusions: Our study has provided clues for the role of TGF-β pathway in immune regulation in patients with solid tumors and revealed the potential predictive role of TGF-β pathway alternation in cancer immunotherapy.

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Granulocytic Expression of CD11b/CD18 and Thrombotic Risk in Patients with Myeloproliferative Neoplasms

Journal of Biomedical and Clinical Research ◽

10.2478/jbcr-2021-0005 ◽

2021 ◽

Vol 14 (1) ◽

pp. 47-52

Author(s):

Doroteya K. Todorieva-Todorova ◽

Katya S. Kovacheva ◽

Nikolay T. Tzvetkov ◽

Svetla O. Blazheva ◽

Tzvetan H. Lukanov

Keyword(s):

Blood Cells ◽

Myeloid Leukemia ◽

Clinical Course ◽

Myeloproliferative Neoplasms ◽

Control Group ◽

Thrombotic Complication ◽

Myeloproliferative Disease ◽

Thrombotic Risk ◽

History Of

Summary Myeloproliferative neoplasms (MPN) are clonal hematological conditions characterized by excessive production of one or more cell lines in the bone marrow. The blood cells produced are often hyperactive in their functions, which could lead to complications in the disorder‘s clinical course. We aimed to define the role of granulocytic CD11b/CD18 expression for the thrombotic risk in MPN patients. We investigated 110 patients with a histologically confirmed diagnosis of a myeloproliferative disease and a control group of 46 healthy volunteers. In the patient group, we found an average expression 4.59 times higher than in the control group. The highest expression was found in a subgroup of patients with polycythemia vera – 71.55% of the patients’ neutrophils. In each subgroup with essential thrombocythemia, myelofibrosis, and chronic myeloid leukemia, the patients with a history of thrombotic complication had a higher expression than the patients without such complications.

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