Expression of chronic myeloid leukemia oncogenes BCR-ABLP210 and BCR-ABLT315I affect cellular and humoral innate immunity in Drosophila melanogaster

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Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm resulting from the BCR-ABL fusion protein coded by the Philadelphia chromosome which results from a reciprocal translocation between the Abelson murine leukemia gene (ABL) on chromosome 9 and Breakpoint Cluster Region gene (BCR) on chromosome 22 (Jabbour and Kantarjian 2018, Nowell and Hungerford 1960, Rowley 1973). This translocation creates the BCR-ABL oncogene which codes for the BCR-ABL fusion protein; a constitutively active tyrosine kinase (Lugo et al. 1990). Tyrosine kinase inhibitors (TKIs) are considered the gold standard treatment for CML patients (Hochhaus et al. 2008). Despite the advancement offered by the first and second-generation TKIs, there are certain resistant BCR-ABL mutant leukemic clones. For instance, the T315I mutation which results from the substitution of Threonine with Isoleucine at the 315th position of ABL imparts resistance to first and second generation TKIs (O'Hare et al. 2011, Barouch-Bentov and Sauer 2011). One TKI that showed efficacy against the T315I mutation is ponatinib (Tanaka et al. 2010, Chan et al. 2012). However, due to its pan-activity on different kinases, ponatinib has severe side effects and high toxicity and is now administered to patients with precaution (Miller et al. 2014). Despite the extensive research on BCR-ABL, the molecular mechanisms and functional interactors in wild-type P210 and T315I mutant background are yet to be fully understood. Conservation between Drosophila melanogaster and mammalian genes (Klein 1997), in addition to the shared homology in proteins that interact with BCR-ABL (Fogerty et al. 1999, Bashaw et al. 2000), suggest that a fly model can be used to understand BCR-ABL genetic interactors (Lo Iacono et al. 2021). We previously validated a CML Drosophila model for drug screening using TKIs. We expressed BCR-ABLP210 and BCR-ABLT315I in Drosophila eyes and observed a rough eye phenotype which was more severe in T315I mutants. Furthermore, we used this eye model to test the efficacy of clinically administered TKIs (Al Outa et al. 2020). Bernardoni et al. showed similar rough eye phenotypes upon expression of BCR-ABLP210 through interaction with endogenous Drosophila Abl (Ena) indicating a conserved signal transduction pathway between humans and flies. In addition, BCR-ABL expression in the hematopoietic precursor cells of the lymph gland affected Drosophila blood cell homeostasis by increasing the number of circulating blood cells (Bernardoni et al. 2019). Nevertheless, the impact of BCR-ABL oncogene on innate immunity is yet to be understood. Fruit flies possess two forms of innate immune responses, cellular and humoral. The cellular response is mediated by Drosophila hemocytes which can be either circulating or sessile. Circulating hemocytes are present in the hemolymph while sessile hemocytes are found in pockets between the epidermis and muscular layers in the larvae (Shrestha and Gateff 1982, Lanot et al. 2001). Circulating hemocytes can be of three types, macrophage-like plasmatocytes, crystal cells, and lamellocytes. Plasmatocytes phagocytose bacteria and apoptotic debris while crystal cells are involved in the melanization process; the latter is analogous to wound healing. Lamellocytes, the largest in size among circulating hemocytes, are very low in number and differentiate only upon parasitic infection (Rizki and Rizki 1980, Franc et al. 1996). The humoral response on the other hand results in the synthesis of antimicrobial peptides (AMPs) and hemolymph coagulation and melanization. Humoral pathways help Drosophila melanogaster discriminate between pathogens based on their surface molecules such that, either one of the NF-κB transcription factors can be activated; Dorsal/Dif or Relish, which are representative of the Toll or IMD pathway, respectively. The JAK/STAT pathway on the other hand was shown to be involved in viral infection whereby Domeless activates the transcription factors Hopscotch and STAT92E, consequently activating the expression of immune and stress-responsive genes such as Tep1 and Tot A (Lemaitre et al. 1997, Lemaitre and Hoffmann 2007). Therefore, the Drosophila’s reductionist hematopoietic and immune system would aid in understanding the role of BCR-ABL expression on the immune response and hematopoiesis in general.

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