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PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alicja M. Gruszkaa, Myriam Alcalay
In addition, in a small percentage of patients (<5%) rare translocations occur. The common denominator of these fusions is the presence of RARa and partner genes include: PLZF, NPM, NuMA and Stat5a; however, for the purpose of this chapter, they will not be discussed any further [42].
JAK-STAT pathway: Testicular development, spermatogenesis and fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
The JAK-STAT pathway has been extensively studied in a wide range of organisms from slime molds to mammals. In mammals, it was originally identified through cytokine (IFNα, IFNγ) and growth factor–induced signaling (7) by which it regulates various cellular events such as cell proliferation, differentiation and apoptosis (1). The components of the JAK-STAT pathway have been identified in a wide range of organisms including Drosophila melanogaster, Caenorhabditis elegans and mammals. In mammals, there are more than 50 cytokine-like molecules that mediate JAK-STAT signaling. The diverse functions of this pathway in different cells are regulated by four JAK family members, i.e., JAK1, JAK2, JAK3 and TYK2, and seven STAT family members, i.e., STAT1, STAT2, STAT3. STAT4, STAT5a, STAT5b and STAT6 (8) (Table 15.1). Because of the numerous JAK and STAT homologues, study of the system is more complex (3,9).
Blastic Transformation of Chronic Myelogenous Leukemia: Does BCR-ABL Orchestrate Disease Progression?
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
Calabretta Bruno, Perrotti Danilo
In contrast, PI-3K and the STAT5 are important pathways required for BCR-ABL transformation and activated in both chronic and blastic phase CML (29,30). BCR-ABL interacts indirectly with the p85 regulatory subunit of PI-3K via various docking proteins, including GRB-2/Gab2 and c-cbl (31). The PI-3K activation via the GRB-2/Gab2 interaction appears pathologically relevant, as Gab2-deficient marrow cells are resistant to BCR-ABL transformation (31). Activation of the PI-3K pathway triggers an Akt-dependent cascade that has a critical role in BCR-ABL transformation and survival of BCR-ABL+ myeloid progenitors (32) by regulation of the subcellular localization and/or activity of several targets, such as BAD, MDM2, IkB-kinase-α, and members of the Forkhead family of transcription factors (33). Consistent with the effects of Akt on many targets, inhibition of the PI-3K/Akt pathway suppresses in vitro colony formation and in vivo leukemogenesis of BCR-ABL-expressing cells (29,32), and marrow cells defective in PI-3K/Akt activation are resistant to BCR-ABL transformation (31). Likewise, several observations suggest the importance of STAT5 in CML. In fact (i) BCR-ABL mutants defective in STAT5 activation were less efficient than the wild-type form in the transformation of 32Dcl3 myeloid precursor cells (34); (ii) a constitutively active STAT5 mutant rescued the leukemogenic potential of STAT5 activation-deficient BCR-ABL mutants (34); and (iii) ectopic expression of a dominant-negative STAT5 mutant suppressed BCR-ABL-dependent transformation of primary mouse marrow cells (34). Furthermore, expression of p210 BCR-ABL in primary murine STAT5A-deficient bone marrow cells, which do not have deficiencies in colony formation, induced a B-ALL or a CML/B-ALL rather than a pure CML chronic phase-like disease in recipient mice (35), suggesting that STA5A is important for BCR-ABL-dependent transformation and development of a CML but not a B-ALL-like disease in mice.
The role of the prolactin receptor pathway in the pathogenesis of glioblastoma: what do we know so far?
Published in Expert Opinion on Therapeutic Targets, 2020
Antonela S Asad, Alejandro J Nicola Candia, Nazareno Gonzalez, Camila F Zuccato, Adriana Seilicovich, Marianela Candolfi
PRL signaling via PRLR long isoform activates multiple kinases, including Janus kinase 2 (JAK2), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), Src family, and the pathways of serine/threonine kinases Nek3-Vav2-Rac1 [47–49]. The main pathway involves JAK2, which in turn activates signal transducer and activator of transcription 5 (STAT5), including STAT5a and STAT5b [40]. In the mammary gland, PRL acts through homodimers of PRLR long isoform to stimulate the differentiation of mammary epithelial cells, via JAK2/STAT5 signaling[40]. MAPK pathway is another important pathway triggered by PRLR that involves the intermediaries Shc/Grb2/Sos/Ras/Raf [40]. The recruitment of PI3K leads to the production of phosphatidylinositol (4,5)-bisphosphate (PIP2) and phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which recruits Akt [40]. PI3K enhancer-activating Akt (PIKE-A) directly associates either with STAT5 or PRLR, which in turn activates STAT5 and its subsequent gene transcription activity [50]. These events induce the expression of many PRL response genes, including those involved in cell proliferation and differentiation. Even though homodimers between PRLR short isoforms are able to mediate JAK2 activation, the short isoform lacks the cytoplasmic sequences required for JAK2/STAT5 activation [42]. Therefore, PRLR short isoforms are unable to activate JAK2/STAT5 pathway, but can activate MAPK and PI3K pathways.
Adverse events, clinical considerations and management recommendations in rheumatoid arthritis patients treated with JAK inhibitors
Published in Expert Review of Clinical Immunology, 2018
Fabiola Atzeni, Rossella Talotta, Valeria Nucera, Francesca Marino, Elisabetta Gerratana, Donatella Sangari, Ignazio Francesco Masala, Piercarlo Sarzi-Puttini
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a signal transducer complex whose dysfunction is associated with an increased risk of developing cancer and inflammatory diseases. Various cytokines, such as interferon (IFN)-α and -β, interleukin (IL)-6, IL-10, IL-12, IL-15, IL-21, and IL-23, transmit intracellular signals by recruiting the JAK/STAT molecular pathway [1]. Seven STAT genes (STAT1, 2, 3, 4, 5A, 5B, and 6) and four JAK genes (JAK1, 2, 3, and TYK2) have been described in mammals. STAT1 and STAT2 participate in IFN-driven immune responses; STAT3 and STAT5A/B favor the survival and activation of various T lymphocytes, including Th17 and T regulatory cells; STAT4 and STAT6 are hallmarks of respectively Th1 and Th2 responses. JAK1 and 2 are involved in mouse neurogenesis and erythropoiesis, whereas JAK3 and TYK2 are more closely involved in the immune system [2]. JAK1, JAK2, and TYK2 are ubiquitously expressed, whereas the expression of JAK3 is restricted to myeloid and lymphoid cells [3]. JAK molecules are closely related to the intra-cytoplasmic tail of receptors interacting with a number mediators, including cytokines, hormones, and peptides. STATs are transcriptional factors with a DNA binding domain and a transcriptional activation domain.
An evaluation of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine as therapy for acute myeloid leukemia
Published in Expert Review of Hematology, 2021
Tamer A. Othman, Matthew E. Tenold, Benjamin N. Moskoff, Tali Azenkot, Brian A. Jonas
Proposed genomic mechanisms of resistance, whether it be primary or acquired, include the birth and/or expansion of a clone harboring mutations that promote AML cell survival [71]. A variety of mutations in different pathways has been described, such as those involved with kinase signaling. These include FLT3-ITD, NRAS and JAK1 mutations. Mutations in U2AF1, U2AF2, SRSF2 and ZRSR2 that lead to alternative RNA splicing have also been reported. Additionally, mutations can occur in cancer-related transcription factors, for instance in IKZF1, SETBP1, RUNX1 and STAT5A. There are also tumor suppressor protein mutations like TP53. Finally, mutations can be seen in epigenetic modifiers, classically BCOR and CREBBP [72]