Development of Multidrug Resistance in Acute Myeloid Leukemia Is Associated with Alterations of the LPHN1/GAL-9/TIM-3 Signaling Pathway

Abstract

P-glycoprotein (known as ABCB1 transporter) expression in myeloid blasts of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) leads to the commonly observed multidrug resistance. Overexpression of latrophilin-1 was detected in leukemic cells from AML patients. In a previous study, we showed that ABCB1 overexpression is associated with decreased latrophilin-1 expression in MOLM-13/VCR and SKM-1/VCR AML cell variants derived from MOLM-13 and SKM-1 cells by vincristine selection/adaptation. In the present study, we found that if ABCB1 overexpression occurs in myeloid blasts of newly diagnosed MDS patients, latrophilin-1 expression is attenuated. Latrophilin-1 may initiate TIM-3- and galectin-9-mediated immune escape. We demonstrated changes in the expression of both proteins by comparing ABCB1-positive cell variants (MOLM-13/VCR, SKM-1/VCR) with their ABCB1-negative counterparts. Galectin-9 was present in our cell lines in eight protein isoforms for which we identified the respective transcription variants resulting from alternative splicing, and we verified their structure by sequencing. The isoform profile of galectin-9 was different between ABCB1-positive and ABCB1-negative cell variants. The interaction partner of galectin-9 is CD44, and its expression was altered in the ABCB1-positive variants MOLM-13/VCR and SKM-1/VCR compared to their ABCB1-negative counterparts.

Serum soluble immune checkpoint levels predict cervical lymph node metastasis of differentiated thyroid carcinoma patients

“…Importantly, the sTIM‐3 secretion levels of T lymphocytes isolated from TILNs were found to increase. Unlike other sICs, such as sGalectin‐9 21 and sPD‐L1, 22 the secretion of sTIM‐3 is currently known to be completely dependent on the proteolytic cleavage of ADAM protease, but independent of alternative splicing of mRNA. 23 Thus, the expression of TIM‐3 on the cell membrane is closely related to the secretion of its soluble form.…”

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure

“…As discussed in this review, lymph nodes (where anti-tumor immune responses are elicited) and the tumor itself (where effector function is performed) are attractive anatomic sites where galectins may be inhibited. Finally, it was demonstrated that tumors generate different isoforms of galectins via alternative splicing [ 379 ]. This phenomenon can induce inhibitor-resistant galectins.…”

Multifunctional Nanoplatforms as a Novel Effective Approach in Photodynamic Therapy and Chemotherapy, to Overcome Multidrug Resistance in Cancer

“…Besides the accumulation of PSs, another important factor affecting the treatment efficacy or failure is the phenomenon of MDR. The concept of MDR is not novel, as it has been very extensively studied over the last few decades [ 10 , 150 , 151 , 152 ]. Initially, only the reduction of chemotherapy efficacy was attributed to MDR [ 10 ], but since the 1990s, there has been a growing body of evidence highlighting the fact that MDR exceeds the borders of chemotherapy and could affect other therapeutic approaches, even PDT.…”