The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases

 Nami McCarty, Ph.D.

Nami McCarty, Ph.D.

Associate Professor, Center for Stem Cell and Regenerative Medicine

Jerold B. Katz Distinguished Professor


Title of research: Deciphering molecular and cellular mechanisms of pathogenesis and drug resistance in human lymphomas and multiple myeloma.

Information about myself and my research: The major goals of my research program are to decipher molecular pathways that confer selective growth and survival advantages to malignant B cells. We are also interested in understanding how stem-like cells contribute to drug resistance in these malignancies. Therefore, I began new lines of studies involving the identification and characterization of stem like cells in MCL (mantle cell lymphoma), termed MCL initiating cells (MCL-ICs).

Mantle cell lymphoma cells

In 2009, I initiated collaborations with clinicians at neighboring M.D. Anderson Cancer Center (MDACC) to obtain multiple MCL patient samples, which we used to prospectively isolate stem-like cells in MCL. cDNA microarray analyses led to discovery of a signaling axis, comprised of NF-kB/ transglutaminase 2 (TG2) signaling, which contribute select survival of MCL-ICs.

These stem-like populations are also highly resistant to drugs that are currently used in the clinics, such as R-CHOP, R-CVAD, R-DHAP and FluBR. These results emphasize that our findings are clinically relevant and further characterization of MCL-ICs may improve patient survival. Another line of research involves understanding how transcription factors that determine normal B cell lineage differentiation are involved in malignant B cell initiation and progression. One of those factors is paired box 5 (PAX5), a determinant of normal B cell lineage development. We discovered that PAX5 silencing in MCL leads to increased tumor formation in vitro and in xenograft mice, indicating that PAX5 is a potential tumor suppressor. We are currently conducting collaborative translational research efforts with clinicians at MDACC to correlate PAX5 levels with relapsed MCL cases and patient survival.

Effects of CXCR4 SilencingWe also conducted high throughput drug screening using libraries comprised of 3991 compounds of NCI oncology, custom clinical, and prestwick libraries. We discovered that select compounds target the survival pathways of PAX5 silenced cells. Given that PAX5 silenced cells are highly drug resistant, discovery of compounds that target drug resistance populations in MCL have direct translational applications. Downstream of PAX5 signaling is BACH2 (BTB and CNC homology), which is another transcription factor that is involved in drug responses in MCL. We discovered that BACH2 nucleo/cytoplasmic shuttling influences resistance to drugs that generate reactive oxygen species (ROS). We have also developed a new line of research studying stem-like cells in multiple myeloma (MM) and their interaction with microenvironment. MM is heterogeneous disease due to their manifestation in the bone marrow compartment. We developed a new technology that can trace stem-like cells in vivo. Staining cells with lipophilic fluorescent dye PKH allows cells to cycle in vivo. Only cells that retain the dye are quiescent stem-like cells. Interestingly, stem-like MM cells preferentially reside within osteoblastic niche rather than vascular and spleen niches. These cells were also drug resistance and contributed to increased tumor formation in the secondary xenograft mice. We conducted gene profiling analyses for the quiescent PKH+ populations and the characterization of PKH+ cells and their interaction with microenvironment is underway. Stem-like cells in MCL or MM are relatively minor populations. Isolation and investigatingcharacteristics of these cells is technically challenging and we have developed systems to make seminal discoveries in the field of B cell cancers.

CXCR4-silenced MCL cells

Ongoing research projects:

a. Stem-like MM cells and microenvironment niche: We conducted microarray analyses to identify genes expressed in quiescent PKH+ cells from osteoblastic, vascular and spleen niches. We will continue to characterize functions of these genes in the MM interaction with bone marrow microenvironment. We will also collaborate with clinicians and basic scientists at MD Anderson to investigate niche competition between stem-like MM cells with hematopoietic stem cells.

b. Development of small molecule inhibitors for targeting advanced lymphomas: We have conducted high throughput chemical screening to identify the compounds that selectively target MCL cells that home to the bone marrow compartment. We will further develop and test these compounds in animal models for pre-clinical studies and plan to test its efficacies in the patients.

c. Delineating transcription factor networks on drug resistant lymphomas: We will continue to address roles for PAX5 signaling in MCL pathogenesis. PAX5 silencing increased bone marrow targeting in vivo and increased drug resistance in MCL. We will analyze PAX5-myc-p53 signaling using mice models of lymphomas and continue to investigate the roles of these signaling in lymphoma spread. Downstream of PAX5 is BACH2 transcription factor, which plays an important role in lymphoma drug resistance. We plan to use genetic silencing to test whether BACH2 has tumor suppressive roles in MCL. We will also closely work with collaborators at MDACC to determine whether BACH2 sub-cellular localization in the cell determine drug resistance outcome and patient survival.

Key publications:

1. Jung, H-J., Zheng, C., Wang, M., Fayad, L., Romaguera, J., Kwak, L.W., and McCarty, N. Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma (MCL) via manipulation of tissue transglutaminase activities. Blood 119:2568-2578, 2012.

2. Jung, H-J., Chen, Z., and McCarty, N. Synergistic antiproliferative effects of arsenic trioxide (ATO) with bortezomib in mantle cell lymphoma (MCL). American Journal of Hematology 87:1057-1064, 2012.

3. Chen, Z., Romaguera, J., Wang, M., Fayad, L., Kwak, L.W., and McCarty, N. Verapamil synergistically enhances cytotoxicity of bortezomib in mantle cell lymphoma via induction of reactive oxygen species production. British Journal of Hematology 159:243-246, 2012.

4. Chen, Z., Pittman, E.F., Romaguera, J., Fayad, L., Wang, M., Neelapu, S.S., McLaughlin, P., Kwak, L., and McCarty, N. Nuclear translocation of B-cell-specific transcription factor, BACH2, modulates ROS mediated cytotoxic responses in mantle cell lymphoma. PLOS one 8(8):e69126.doi:10.1371/journal.pone.0069126, 2013.

5. Chen, Z., Orlowski, R.Z., Wang, M., Kwak, L., and McCarty, N. Osteoblastic niche supports the growth of quiescent multiple myeloma cells. Blood 123: 2204-2208, 2014.

6. Teo, A.E., Chen, Z., Miranda, R.N., McDonnell, T., Medeiros, L.J., and McCarty, N. Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1. Leukemia 15. doi: 10.1038/leu.2015.140. [Epub ahead of print], 2015