Dipartimento di Patologia Sezione di Patologia Generale Universit

Dipartimento di Patologia Sezione di Patologia Generale Università di Verona

Granulocyte/macrophage progenitors Megakaryocyte/erythrocyte progenitors Common myeloid progenitors Haematopoietic stem cell Chronic myeloid leukemia-blast phase (70%) Common lymphoid progenitors Chronic myeloid leukemia-blast phase (30%) Chronic myeloid leukemia-chronic phase R. Ren, 5: 172 -183

Weisberg et al. 7: 345, 2007 With the aid of several mediator proteins, BCR-ABL associates with Ras and stimulates its activation. The adaptor protein, growth factor receptor-bound protein 2 (GRB 2), interacts with BCR-ABL through the proximal SRC homology 2 (SH 2)-binding site that develops when the tyrosine 177 (Y 177) residue of BCR-ABL is autophosphorylated. GRB 2, when bound to BCR-ABL, interacts with the son of sevenless (SOS) protein. The resulting BCR–ABL–GRB 2 –SOS protein complex activates Ras. The adaptor proteins CRKL (CRK-like) and SHC (SH 2 -containing protein) can also mediate the BCR-ABL activation of Ras and the mitogen activated protein kinase (MAPK) pathway are coupled by Raf (a serine/threonine kinase). Raf catalyses the phosphorylation of the mitogen-activated and extracellular-signal regulated kinases 1 and 2 (MEK 1 and MEK 2); this results in their activation. Through the stimulation of the Ras–Raf pathway, BCR-ABL increases growth factor-independent cell growth. BCR-ABL also associates with and activates the phosphatidylinositol-3 kinase (PI 3 K) pathway, suppressing programmed cell death and increasing cell survival. BCR-ABL is associated with components of the focal adhesion(that is, actin, paxillin and focal adhesion kinase, or FAK); the activation of CRKL–FAK–PYK 2 leads to a decrease in cell adhesion. BCR-ABL also associates with the Janus kinase and signal transducer and activator of transcription (JAK–STAT) pathway. Finally, BCRABL activates pathways that lead to atypical responses to chemotactic factors, which leads to an increase in cell migration. BCR-ABL also associates with survival proteins that interact with the mitochondrial-based BCL 2 family. CAS, p 130 CRK-associated substrate; GAB 2, GRB 2 -associated binding protein 2; SHIP, SH 2 -containing inositol-5 -phosphatase

(Imatinib mesilato)

S = stem cell P = progenitori leucemici D = cell leucemiche differenziate TD = cellule differenziate e mature

Fig. 1. First- and second-generation tyrosine kinase inhibitors for cancer treatment Sindrome ipereosinofilica Doppio inibitore attivo sia su Abl che su Src J. Baselga Science 312, 1175 -1178 (2006) Published by AAAS

Fig. 1. First- and second-generation tyrosine kinase inhibitors for cancer treatment Membro di famiglia erb. B di recettori per fattori di crescita (comprende EGF-R e altri). Gene amplificato nel 25% dei tumori mammari primari di tipo invasivo Sindrome ipereosinofilica Ab monoclonale J. Baselga Science 312, 1175 -1178 (2006) Published by AAAS

TRASDUZIONE DEL SEGNALE DA PARTE DI RECETTORI IMMUNI ITAM (Immunoreceptor tyrosine-based inhibitory motif) : DExx. Yxx. L/I(x)6 -7 Yxx. L/I

Fcg. RIIA ITAM Fcg. RIIB ITIM: I/Vxx. Yxx. L/V Immunoreceptor tyrosine-based inhibitory motif

TRASDUZIONE DEL SEGNALE DA PARTE DI RECETTORI IMMUNI

attivazione

C-type lectins

Lyn Fyn/ Lck ZAP 70 Lyn Syk Lyn/Hck/Fgr Syk

Fig. 1. Signal transduction by classical immunoreceptors C. L. Abram et al. , Sci. STKE 2007, re 2 (2007) Published by AAAS

Abl

Lipide fosfatasi

Protein fosfatasi

ANCHE ALCUNE FAMIGLIE DI INTEGRINE (b 2 E b 3) TRASDUCONO IL SEGNALE MEDIANTE UN MODULO BASATO SU ADATTATORI CON SEQUENZA ITAM E SYK ITAM ? YP YP SYK SFK

GAF: gamma activated factor GAS: gamma activation sequence ISRE: interferon stimulated response element IRF: interferon regulatory factor ISGF 3: interferon stimulated gene factor 3