Development Of Multidrug Resistance In Acute Myeloid Leukemia Is Associated With Alterations Of The Lphn1/Gal-9/Tim-3 Signaling Pathway

Simple Summary Latrophilin-1 is a latrotoxin receptor and is commonly found in the plasma membrane of neurons. This receptor has recently been identified in the plasma membrane of myeloid leukemia blasts but not in healthy leukocytes. We have shown that the development of drug resistance associated with ABCB1 overexpression leads to decreased regulation of latrophilin-1 in human acute myeloid leukemia cell lines. Here, we proved that latrophilin-1 expression also occurs in the myeloid blasts of patients newly diagnosed with myelodysplastic syndrome when ABCB1 is overexpressed. Furthermore, we provided the evidence that in case of ABCB1 overexpression in human acute myeloid leukemia cell lines, changes in the expression of latrophilin-1-regulated proteins occur that are thought to allow myeloid blasts to escape control of the immune system. All of the above changes in protein expression appear to be involved in the overall altered phenotype of neoplastic myeloid cells following ABCB1-mediated MDR development. 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.