BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

Abstract

Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL þ leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K þ T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.

Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2–harboring clones as main relapse-driving force in childhood ALL

“…5 A remote alternative explanation for an independent role of minor P2RY8-CRLF2-positive clones would be that they alone could perhaps render their fusion-negative leukemic counterparts resistant through a paracrine route in a similar manner as has been demonstrated for minor mutant BCR-ABL-positive clones in comparable situations. 30 However, the absence of P2RY8-CRLF2-positive clones in most relapses hardly supports such a possibility.…”

Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile

“…20 Paracrine protection of imatinib-sensitive leukemic cells by low levels of imatinib-resistant cells with BCR-ABL1 mutations has also been reported. 21 A recent study found no correlation between the number of low-level mutations (detection limit 1%) in tyrosine kinase inhibitornaïve, Philadelphia chromosome-positive acute lymphoblastic leukemia patients and the likelihood of relapse when taking dasatinib. 22 However, only 15 patients were studied, and all had Ն 2 mutations, which may signify high clonal diversity in these patients.…”

The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors

“…This can be achieved either by the acquisition of mutations rendering the inhibitor ineffective or by activating a kinase distinct from the one being inhibited. [20][21][22][23] Thus, targeting STATs holds the promise of being useful against a wide spectrum of tumors, and for decreasing the emergence of resistance to kinase inhibitors.…”