Characterization of NUP205 as a haploinsufficient essential gene for the treatment of hematopoietic malignancies

PROJECT SUMMARY/ABSTRACT Complete or partial loss of chromosome 7 (-7/del(7q)) predisposition syndromes, preleukemia, and leukemia. is the most common cytogenetic abnormality in It is associated with short overall survival and chemotherapy resistance. Given their high prevalence and unfavorable prognosis, there is an urgent need to

identify more effective and innovative therapies. Nonetheless, the pathogenesis and therapeutic vulnerabilities of -7/del(7q) remain undetermined. We hypothesize that the hemizygous deletion of one or more haploinsufficient essential genes on chromosome 7q is responsible for ineffective hematopoiesis, akin to the partial loss of ribosomal proteins in 5q

deletion myelodysplastic syndrome (MDS) and inherited BM failure syndromes. Such a hemizygous deletion may create specific vulnerabilities that could be therapeutically targeted by further inhibiting the encoded protein, a related protein, or an associated pathway. Nuclear pore complexes (NPCs) play a crucial role in regulating several vital cellular processes by

controlling the nuclear-cytoplasmic trafficking of RNA, ribosomes, transcription regulators, and drug targets. We conducted comprehensive statistical analyses and individual CRISPR knockout experiments, which revealed NUP205, an NPC member, to be a haploinsufficient essential gene on chromosome 7q. Knockout or knockdown

of NUP205 results in a growth disadvantage or cell apoptosis in a dose-dependent manner. NUP205 hemizygous deletion single-cell clones exhibit resistance to cytarabine and increased sensitivity to elesclomol, consistent with the drug profile of -7/del(7q) primary leukemia samples in the Beat AML cohort. Therefore, we hypothesize that

the deletion of the haploinsufficient essential gene NUP205 contributes to the BM insufficiency phenotype observed in -7/del(7q) patients and can be therapeutically targeted using elesclomol-based treatments to specifically eliminate malignant cells harboring -7/del(7q). We propose here: (1) to investigate the functional impacts of NUP205 on hematopoiesis; (2) to elucidate

the mechanisms of NUP205 deletion-mediated impacts on cellular activity and chemosensitivity; (3) to investigate elesclomol combination therapies targeting leukemia cells harboring -7/del(7q). Collectively, our studies will elucidate the cellular and molecular mechanisms of NUP205 deletions in driving

the BM insufficiency phenotype, creating specific vulnerabilities, and shaping the drug responses for subsets of myeloid malignancies. Ultimately, this effort will provide a basis for further translational work and the development of promising inhibitors for clinical testing. Additionally, our study will serve as a prototype for

identifying novel therapeutic vulnerabilities for other chromosome deletions in hematological malignancies.