Morgan Lab Research Initiatives | NYU Langone Health

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Morgan Lab Research Morgan Lab Research Initiatives

Morgan Lab Research Initiatives

The Morgan Lab explores the genetic basis of multiple myeloma and clinically aggressive myeloma, inherited genetic risk factors for myeloma, and possible reasons for the excess of myeloma in African Americans.

The Genetic Basis of Multiple Myeloma

Our laboratory has delivered many key insights into current understandings of the genetic basis of myeloma. As a consequence of this work we have established large datasets of gene expression, exome sequencing and whole genome sequencing with which we can explore the pathogenic basis of the disease.

We have shown that myeloma is not a single disease, but is rather composed of up to six subsets that have different biological features, each of which can be therapeutically targeted. We have identified genetic drivers of the disease subsets and have also identified the important role of activation of the RAS and NFkB pathways.

A spectrum of the most common genetic variants associated with multiple myeloma comprises a small set of recurrent mutations and a long tail of rare variants. NRAS, CCND1, MYC, KRAS, followed by DIS3, MMSET, BRAF and FAM46C are relatively more frequent than the other mutated genes.

More recently we have focused on the non-coding regions of the genome and the impact that structural chromosomal events have on disease pathogenesis and clinical outcome.

New chromosomal structure formation in multiple myeloma. (A) FISH and SKY staining of a metaphase cytogenetic spread formed as a result of a complex structural rearrangement. (B) CIRCOS plot of a complex chained rearrangement. (C) CIRCOS plot showing chromothripsis. (D) Copy number plot of the fusion region of a complex structural event showing copy number oscillation.

This work led us to identify fusion genes that can be targeted therapeutically. We have gone on to investigate the pathogenic role of genes deregulated as a consequence of super-enhancer rearrangement by structural variants.

CIRCOS plots of (A) the spectrum of Ig gene rearrangements in multiple myeloma, and (B) structural rearrangements to MYC driving its overexpression. (C) A set of novel genes upregulated by rearrangement to super-enhancers in multiple myeloma. (D) Boxplots showing the level of expression of genes with and without rearrangement to a super enhancer.

Importantly, the disruption of topologically associated domain (TAD) boundaries plays a critical role in gene deregulation in myeloma and, in this respect, we are investigating the role played by the t(4;14) which deregulates NSD2, a histone methyl-transferase, resulting  in widespread epigenetic deregulation. Exploring structural lesions further, more recently, we have been studying the role played by complex structural events such as chromoplexy, chromothripsis and templated insertions. The complex nature of these structural events means they can deregulate more than one gene simultaneously, deliver a strong oncogenic drive and, as a consequence, mediate punctuated evolution and adverse clinical outcomes.

The Genetic Basis for Clinically Aggressive Myeloma

A key challenge therapeutically is to improve the outcome of high-risk myeloma, a sub group that has seen little improvement in outcome over the last decade. There are only limited molecular events which contribute to this type of behavior and we have identified many of them. This has allowed us to show that integrating molecular diagnostics into clinical risk stratification systems can enhance our ability to detect high-risk behavior at clinical presentation. Being able to do this accurately now allows us to select patients for trials focused on high-risk cases, though there is much more to learn about high-risk behavior and how we can design new treatments specifically able to target it. To achieve this, we are using single cell analysis, genetic segmentation and precision immunotherapy to develop and selectively apply new agents.

Genetic Risk Factors for Myeloma and its Excess in African Americans

In collaboration with a number of European centers, we have been able to identify many of the most important inherited genetic risk factors contributing to the risk of developing of myeloma. In addition to inherited variants, which associate with the risk of myeloma, we are applying “mutographs” or signatures of environmental exposures to gain insights into pathogenic mechanism active in the early phases of myeloma development. We are using this successful approach to study the hypothesis that the excess of myeloma in African Americans is the result of an inflammatory bone marrow state.