SİNYAL İLETİ SİSTEMİ VE HEMATOLOJİK MALİGNİTELER Uzm.Dr. Güray Saydam Ege Üniversitesi Tıp Fakültesi Hematoloji Bilim Dalı

SİNYAL İLETİMİNİN GENEL ŞEMASI Growth factor Hormone Cytokine Death factor Ligand Multispan GTPase linked Tyrosine kinases Serine/threonine kinases Integrins Cytokine receptors Nuclear receptors Receptor Scaffolds, Adaptors Kinases, Phosphatases Lipases, GTPases Transcription regulators, Chromatin remodelers Cytoskeletal reorganizers Intracellular signal cascade Transcription, Translation Metabolism, Migration Cell cycle arrest, Replication Secretion, Death Transformation (Cancer) Cellular response

Fosforilasyon ve defosforilason Serine Threonine Tyrosine Histidine

AKUT LÖSEMİLER Etiyopatogenetik olarak sinyal ileti sisteminin rolü Tedavide, hedef olarak sinyal ileti sistemi

Jak/Stat Signaling Pathway T(9;12)(p24;p13) TEL/JAK2 Akut Lösemi HTLV-1 JAK aktivasyonunda artış The Jak/Stat Signaling Pathway A wide variety of extracellular signals activate the Stat (signal transducers and activators of transcription) class of transcription factors. Cytokines, lymphokines, and growth factors all signal through a related superfamily of cell surface receptors that are associated with and activate Janus kinases (Jaks). Ligand-induced dimerization of the receptor induces the reciprocal tyrosine phosphorylation of the associated Jaks, which, in turn, phosphorylates tyrosine residues on the cytoplasmic tail of the receptor. These phosphorylated tyrosines serve as docking sites for the Src Homology-2 (SH-2) domain of the Stat protein, and Jak catalyzes the tyrosine phosphorylation of the receptor-bound Stat. Phosphorylation of Stat at a conserved tyrosine residue induces SH-2-mediated homo- or heterodimerization, followed by translocation of the Stat dimer to the nucleus. Stat dimers bind to specific DNA response elements in the promoter region of target genes to activate gene expression. APS (adaptor molecule containing pleckstrin homology and SH-2 domains) can inhibit the Jak-Stat pathway by binding to the cytoplasmic domain of the receptor where it is phosphorylated (activated) by Jak. Activated APS binds to c-Cbl and blocks Stat activation. References Wakioka, T., et al., APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. Leukemia 13, 760-767 (1999). Schindler, C., Cytokines and JAK-STAT signaling. Exp. Cell Res. 253, 7-14 (1999).

STAT-1: IFN’un antiproliferatif etkisi STAT-5: IL-3 ve GM-CSF’in proliferatif etkisi STAT-3: IL-6 ve IL-10’a bağlı büyüme inhibisyonu STAT inhibisyonu: SOCS PIAS

Reseptör Tyrosine Kinazlar Class I:EGFR Class II:IGFR Class III:PDGFR, FLT3R, KIT Class IV: FGFR

RAS Sistemi Ras proteini membrana bağlı reseptör tirozin kinaz aktivitesini sitoplazmik yolaklara ileten guanin nukleotid bağlama özelliği olan bir proteindir. Ras aracılı sinyali sitoplazmik alana ileten en iyi tanımlanmış protein raf’dır. Raf, ras’ı MAP kinazlara bağlayan bir serin / treonin kinazdır. Farklı ras proteinlerinin mutasyonları malignitede önemli rol oynarlar.

MAP Kinaz Sistemi MAP kinaz, mitogen-activated protein kinase demektir. Aynı zamanda extracellular signal regulating kinases (ERK) olarak da bilinir. MAP kinaz dual fosforilasyon ile aktive olur ve PP2a ya da CD45 tarafından inaktive edilir. Bu aile membran reseptör tirozin kinazları aktive eden mitojenik sinyalin nukleusa ulaşımında önemli rol oynamaktadır.

MAP kinase ileti sistemi MAP-kinase-kinase-kinase MAP kinase ileti sistemi MAP-kinase-kinase MAP-kinase changes in protein activity changes in gene expression

Myeloid lösemilerde RAS mutasyonları AML %15-30 MDS Fazına bağlı olarak %5-40 JCML %20-30 CMML %30-50 CML nadir

Kronik Lösemiler KML KLL CD20

KLL

Myeloma

Nuclear Factor kappa B ( NF-κB ) 2 domains: one binds DNA; the other activates transcription by interacting with other components of the transcriptional machinery. Have specific motifs in their DNA binding domains e.g. zinc fingers, leucine zippers, helix-loop-helix and helix-turn-helix

NF-κB Involved in various aspects of the immune response Target of Protein Kinase C signalling as well as other pathways Activity is regulated by translocation from cytoplasm to nucleus In inactive form, NF-kB is complexed to its inhibitory subunit I kappa B (IkB) in the cytoplasm Activation of various pathways leads to phosphorylation of IkB, which targets it for proteolytic degradation. Destruction of the inhibitory subunit allows NF-kB free to move to the nucleus where it activates genes.

IKK Cell Survival Immune Responses Stress Responses Development Bacterial Bacterial Products Viruses Inflammatory Cytokines Physiological Stress Physical Stress Oxidative Stress Chemicals Mitogens Growth Factors Hormones IKK P P IkB Proteasome IkB NFkB NFkB NFkB Nucleus Transcription Immune Responses Stress Responses Cell Survival Development

Myeloma

Bortezomib’in myelomda etki mekanizması

Arsenic Trioxide ve myelom