Therapy-related myelodysplasia or acute myelogenous leukemia (t-MDS/AML) is a dreaded complication and the most common cause of non-relapse mortality in patients undergoing autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Previous studies indicate that t-MDS/AML results from damage to hematopoietic stem cells from genotoxic cancer treatment. However, the sequential cellular and molecular changes leading to development of t-MDS/AML are not known. We are conducting a prospective, longitudinal study of patients with HL and NHL undergoing aHCT, in order to gain insight into the pathogenesis and identify predictors of susceptibility to t-MDS/AML. Patients are being followed longitudinally from pre-aHCT to five years post-aHCT, with serial banking of peripheral blood (PB) and bone marrow (BM) samples at pre-determined time-points. The known timing and nature of genotoxic exposures for management of HL or NHL, together with banking of sequentially obtained samples, provides a unique opportunity to study sequential molecular and cellular changes In this liigh-risk population. We are exploring the hypothesis that defects in DNA repair, DNA damage response and increased proliferative demand on HSC that have already acquired DNA damage may contribute to genomic instability and emergence of a malignant clone. Studies conducted during the previous grant period have indicated a role for accelerated telomere shortening and abnormal regulation of hematopoietic stem cell proliferation in the pathogenesis of t-MDS/AML and support this hypothesis. Our previous studies have also resulted in development of methodologies to evaluate DNA repair and acquisition of chromosomal aberrations in primary hematopoietic cells. We propose to build upon our previous findings and systematically investigate the role of these mechanisms in the pathogenesis of t-MDS/AML, with an overarching goal of developing biomarkers of enhanced risk of t-MDS/AML.
We aim to understand the mechanisms and significance of DNA repair defects, altered telomere regulation and acquisition of cytogenetic lesions in the pathogenesis of t- MDS/AML;and to understand the interaction of these abnormalities, therapeutic exposures and demographic variables in determining risk of t-MDS/AML. Successful completion of these studies will provide insights into the pathogenesis of t-MDS/AML and allow accurate assessment of risk factors associated with the development of t-MDS/AML. Early identification of high-risk populations may aid in modification of treatment regimens to reduce risk of this complication.
Therapy-related myelodysplasia or acute myelogenous leukemia (t-MDS/AML) is a dreaded complication of treatment in patients undergoing autologous hematopoietic cell transplantation (aHCT) for lymphoma. The proposed studies will provide insights into the pathogenesis of t-MDS/AML and allow identification of risk factors and biomarkers for development of this complication. Early identification of high-risk populations may guide modification of treatments to reduce risk of t-MDS/AML or application of novel preventive strategies.
|Herrmann, Andreas; Lahtz, Christoph; Nagao, Toshikage et al. (2017) CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity. Cancer Res 77:5118-5128|
|Herrera, Alex F; Mei, Matthew; Low, Lawrence et al. (2017) Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation. J Clin Oncol 35:24-31|
|Kortylewski, Marcin; Moreira, Dayson (2017) Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities. Cancer Immunol Immunother 66:979-988|
|Herrera, Alex F; Armand, Philippe (2017) Minimal Residual Disease Assessment in Lymphoma: Methods and Applications. J Clin Oncol 35:3877-3887|
|Won, Haejung; Moreira, Dayson; Gao, Chan et al. (2017) TLR9 expression and secretion of LIF by prostate cancer cells stimulates accumulation and activity of polymorphonuclear MDSCs. J Leukoc Biol 102:423-436|
|Gibson, Christopher J; Lindsley, R Coleman; Tchekmedyian, Vatche et al. (2017) Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J Clin Oncol 35:1598-1605|
|Herrera, Alex F; Rodig, Scott J; Song, Joo Y et al. (2017) Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma. Biol Blood Marrow Transplant :|
|Urak, Ryan; Walter, Miriam; Lim, Laura et al. (2017) Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy. J Immunother Cancer 5:26|
|Zhang, Chunyan; Xin, Hong; Zhang, Wang et al. (2016) CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer. Immunity 44:913-923|
|Beharry, Andrew A; Lacoste, Sandrine; O'Connor, Timothy R et al. (2016) Fluorescence Monitoring of the Oxidative Repair of DNA Alkylation Damage by ALKBH3, a Prostate Cancer Marker. J Am Chem Soc 138:3647-50|
Showing the most recent 10 out of 88 publications