High-Throughput CRISPR Screening in Hematological Neoplasms

Abstract

CRISPR is becoming an indispensable tool in biological research, revolutionizing diverse fields of medical research and biotechnology. In the last few years, several CRISPR-based genome-targeting tools have been translated for the study of hematological neoplasms. However, there is a lack of reviews focused on the wide uses of this technology in hematology. Therefore, in this review, we summarize the main CRISPR-based approaches of high throughput screenings applied to this field. Here we explain several libraries and algorithms for analysis of CRISPR screens used in hematology, accompanied by the most relevant databases. Moreover, we focus on (1) the identification of novel modulator genes of drug resistance and efficacy, which could anticipate relapses in patients and (2) new therapeutic targets and synthetic lethal interactions. We also discuss the approaches to uncover novel biomarkers of malignant transformations and immune evasion mechanisms. We explain the current literature in the most common lymphoid and myeloid neoplasms using this tool. Then, we conclude with future directions, highlighting the importance of further gene candidate validation and the integration and harmonization of the data from CRISPR screening approaches.

Keywords: CRISPR; algorithms; hematological neoplasms; libraries; resistances; vulnerabilities.

Figure 1

Drug resistance mechanisms identified by CRISPR screening in the main hematological malignancies, reviewed in this work. Diseases are in the inner circle (AML, acute myeloid leukemia; CLL, chronic lymphoblastic leukemia; MM, multiple myeloma; ALL, acute lymphoblastic leukemia); therapies are in the middle circle (IMIDS, immunomodulatory drugs; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone); main pathways, in which each set of validated genes is involved, are in the outer ring. In green, the loss of the gene produces the gain of resistance; in red, the overexpression of the gene produces drug resistance.

Figure 2

Most relevant CRISPR-screening studies in the field of hematology, discussed in this review. The double strand of DNA represents a temporary line. The different hits are represented inside a Cas nuclease scheme in chronological order and classified by diseases: AML, acute myeloid leukemia; NHL, non-Hodgkin-Lymphoma; CLL, Chronic lymphoblastic leukemia; MM, multiple myeloma; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome.