SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome–positive cells derived from patients with chronic myeloid leukemia

Abstract

We prove that the SH2-containing tyrosine phosphatase 1 (SHP-1) plays a prominent role as resistance determinant of imatinib (IMA) treatment response in chronic myelogenous leukemia cell lines (sensitive/ KCL22-S and resistant/KCL22-R). Indeed, SHP-1 expression is significantly lower in resistant than in sensitive cell line, in which coimmunoprecipitation analysis shows the interaction between SHP-1 and a second tyrosine phosphatase SHP-2, a positive regulator of RAS/MAPK pathway.In KCL22-R SHP-1 ectopic expression restores both SHP-1/SHP-2 interaction and IMA responsiveness; it also decreases SHP-2 activity after IMA treatment. Consistently, SHP-2 knocking-down in KCL22-R reduces either STAT3 activation or cell viability after IMA exposure. Therefore, our data suggest that SHP-1 plays an important role in BCR-ABL-independent IMA resistance modulating the activation signals that SHP-2 receives from both BCR/ABL and membrane receptor tyrosine kinases. The role of SHP-1 as a determinant of IMA sensitivity has been further confirmed in 60 consecutive untreated patients with chronic myelogenous leukemia, whose SHP-1 mRNA levels were significantly lower in case of IMA treatment failure (P < .0001). In conclusion, we suggest that SHP-1 could be a new biologic indicator at baseline of IMA sensitivity in patients with chronic myelogenous leukemia. (Blood. 2011;118(13): 3634-3644) IntroductionImatinib (IMA)-targeted inhibition of BCR-ABL is considered the standard front-line therapy for chronic myelogenous leukemia (CML). 1 Although most patients respond to the therapy, primary or acquired resistance to IMA may occur during treatment. 2,3 In addition, the depth of response to the therapy is highly variable: most patients achieve complete cytogenetic remission (CCyR), whereas a more restricted number of them obtains major molecular remission (MMR) and even fewer complete molecular remission. Until now, knowledge of resistance mechanisms is still limited: acquisition of mutations within the kinase domain of BCR-ABL is the main known and common mechanism of resistance. 4 However, ABL mutations seem to be particularly frequent only in acquired resistance or in advanced phases of CML, instead it is less common in front-line resistance. Various BCR-ABL-independent mechanisms of IMA resistance have been proposed, and it is possible that a complex phenomenon of resistance might be sustained by still unknown BCR-ABL-independent molecular mechanisms. [5][6][7] SHP-1 and SHP-2 are two SH2-containing tyrosine phosphatases involved in cell growth regulation. Although they share significant overall sequence identity, they often seem to have opposite biologic functions. 8,9 Indeed, SHP-1 has been described as a negative signal transducer, whereas SHP-2 is a positive regulator of signaling pathways. Note, both SHP-1 and SHP-2 play a role in hematopoietic neoplasias.The activated form of SHP-2, involving phosphorylation at Tyr542 and Tyr580, 10 is associated with GAB1, which is a critical factor to sustain ERK activation downstream of se...

A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia

“…There was no clinically relevant pharmacokinetic interaction between veliparib and temozolomide and the pharmacokinetics appeared to be linear, similar to single-agent studies in solid malignancies (37, 38). This is in contrast to our study of veliparib plus topotecan/carboplatin in poor-risk myeloid malignancies, where non-linear pharmacokinetics were observed above veliparib doses of 80 mg twice daily for 9–14 days (39). A possible explanation for the difference in pharmacokinetics between the two regimens could be an impact of topotecan/carboplatin on renal elimination, resulting in prolonged veliparib exposure (38, 40) that is not seen with temozolomide.…”

STAT3 Mediates Regorafenib-Induced Apoptosis in Hepatocellular Carcinoma

“…We proved that regorafenib directly targets SHP-1 to inactivate the STAT3-mediated signaling pathway and induces anti-HCC activity in vitro and in vivo, suggesting that SHP-1 may be a druggable protein for the treatment of HCC. Similarly, Nicola and colleagues (15) reported that SHP-1 expression determines the resistance to imatinib for chronic myelogenous leukemia treatment and lower levels of SHP-1 were also found in patients with imatinib treatment failure. In light of these findings and this study, we propose that patients with HCC with lower expression of SHP-1 may be more resistant to regorafenib than those patients with higher SHP-1 expression.…”

Global methylation and promoter-specific methylation of the P16, SOCS-1, E-cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission

“…They regulate a variety of cellular processes including cell growth, differentiation, oncogenic transformation and the mitotic cycle. SHP-1 is expressed in normal lymphoid cells, but is lost in a number of types of hematologic malignancies due to epigenetic silencing (45,46). It has been demonstrated that loss of SHP-1 directly contributes to the constitutive activation of STAT3 in MM, chronic myeloid leukemia and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (47).…”