Dasatinib-responsive Chronic Lymphocytic Leukemia in a Patient Treated for Coexisting Chronic Myeloid Leukemia

Abstract

We herein present a case of concurrent chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Two different clones, a Philadelphia (Ph) clone and a CLL clone with a 13q deletion, were identified using fluorescent in situ hybridization. Dasatinib was administered to inhibit Bcr-Abl and Lyn kinase. The patient exhibited a molecular response for CML and a partial response for CLL. To our knowledge, this is the first report to describe the occurrence of a gradual increase in the Bcr-Abl transcript level prior to the diagnosis of Ph-positive CML in an individual with CLL who was successfully treated with dasatinib as the first-line therapy.

Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A

“…Because Lyn-targeting drugs, such as dasatinib, 14,15 have yielded disappointing results in managing CLL, [16][17][18][19] we have recently focused on the substrates of the cytosolic pool of Lyn to better dissect the mechanisms contrasting apoptosis and possibly extend the repertoire of pharmacologic targets of this disease. 13 In the present study, we used Lyn inhibitors as tools to identify novel players whose function might be altered by the constitutive activity of Lyn and to verify a possible role thereof as therapeutic targets.…”

“…In CLL cells, Lyn is overexpressed and distributed into 2 pools, one associated beneath the cell surface and the other bound to an aberrant cytosolic complex, which exhibits the constitutive activation responsible for the phosphorylation of a myriad of protein targets in the cytosol and for the resistance of CLL cells to apoptosis. [11][12][13] Because Lyn-targeting drugs, such as dasatinib, 14,15 have yielded disappointing results in managing CLL, [16][17][18][19] we have recently focused on the substrates of the cytosolic pool of Lyn to better dissect the mechanisms contrasting apoptosis and possibly extend the repertoire of pharmacologic targets of this disease. 13 In the present study, we used Lyn inhibitors as tools to identify novel players whose function might be altered by the constitutive activity of Lyn and to verify a possible role thereof as therapeutic targets.…”

Targeting B-Cell Receptor Signaling in Leukemia and Lymphoma: How and Why?

“…Similar observations were made when Lyn was depleted with siRNA, and therapeutic potential is strongly suggested by xenograft studies showing that tumor size in the mice injected with BTZ-resistant MCL cells can be significantly reduced by dasatinib treatment [153]. In humans there is at least one case report showing that a CLL patient with co-existing chronic myeloid leukemia could be successfully treated with dasatinib [154], suggesting that general targeting of SFKs may be an effective approach. In this light, specific inhibition of Lyn may be a controversial target in the therapy of B-cell malignancies [155,156] because of its role as a positive and negative regulator of BCR signaling [157,158] through its ability to phosphorylate both ITAMs and ITIMs [155].…”

A Case of Chronic Lymphocytic Leukaemia Occurring During Treatment of Chronic Myeloid Leukaemia

“…To literature data, only 21 patients were diagnosed with CLL prior to CML or both simultaneously, and only in 6 patients were diagnosed prior CML to CLL [1][2][3][4][5][6][7]. Patients with diagnosis of CLL have predisposition for occurrence secondary malignancies because of impaired immune system or hemiotherapy [8].…”

“…Second generation of TKI, dasatinib, has the similar effect like imatinib mesilate in treatment of CML. They inhibit pan-Src kinases and suppress leucemogenesis [2]. Kinases from Src family, including Lyn kinases, are exprimed in high concentrations in patients with CLL and have important role in proliferation and surviving malignant cells [16].…”