Mutational Landscape of Clonal Hematopoiesis and Myeloid Cancers

With the advent and use of next generation sequencing on increasing numbers of individuals, the mutational landscape in blood cells, including which genes are mutated, how they are mutated, and how commonly they are mutated, is becoming clearer. We now know that different organismal and cellular stresses, either endogenous or exogenous, can select for very different mutational patterns.

Clonal Hematopoiesis is the Ultimate Genome-Wide Screen

As somatic mutations arise in hematopoietic stem cells, those that confer a fitness advantage relative to non-mutated cells may be selected for in the presence of both extrinsic and intrinsic pressures. Therefore, well designed human genetic studies may uncover important relationships between various selective pressures and specific patterns of clonal hematopoiesis. We utilize this approach to define biologically testable hypothesis in the lab with the goal of defining the biological drivers of these observations. The same approaches can be used in the context of myeloid malignancies including myelodysplastic syndrome or acute myeloid leukemia to understand.

 

Clonal Hematopoiesis, MDS, Leukemia, and Cancer Therapy

In patients heavily pretreated for lymphoma or myeloma, we found that exposure to chemotherapy and radiation selects for mutation in genes involved in the DNA damage response including PPM1D and TP53 whereas exposure to immune checkpoint blockade does not (1,2). We are extending these studies to understand how these mutations ultimately lead to the development of myelodysplastic syndrome and leukemia.

Three Key Questions:


1) What specific exposures are linked to the selection of specific mutational patterns in hematopoiesis and leukemia?

2) How does the exposure-mutational pattern relationship inform deeper aspects of how normal and leukemia cells respond to environmental changes?

3) Can understanding these relationships inform prognostic or therapeutic decision-making for patients with clonal hematopoiesis or blood cancers?

Selected References

(1) Clonal Hematopoiesis in Young Women Treated for Breast Cancer (Pubmed)
Gibson CJ, Fell G, Sella T, Sperling AS, Snow C, Rosenberg SM, Kirkner G, Patel A, Dillon D, Bick AG, Neuberg D, Partridge AH, Miller PG.
Clinical Cancer Research. 2023. Apr 28:CCR-23-0050

(2) Clonal Hematopoiesis in Older Patients with Breast Cancer Receiving Chemotherapy (Pubmed)
Mayerhofer C, Sedrak MS, Hopkins JO, Li T, Tayob N, Faggen MG, Sinclair NF, Chen WY, Parsons HA, Mayer EL, Lange PB, Basta AS, Perilla-Glen A, Lederman RI, Wong AR, Tiwari A, McAllister SS, Mittendorf EA, Gibson CJ, Burstein HJ, Kim AS, Freedman RA, Miller PG.
Journal of the National Cancer Institute. 2023. Apr12:djad065

(3) Clonal Hematopoiesis in Patients Receiving Chimeric Antigen Receptor T-Cell Therapy (Pubmed)
Miller PG*, Sperling AS*, Brea EJ, Leick MB, Fell GG, Jan M, Gohil SH, Tai Y, Munshi NC, Wu CJ, Neuberg DS, Maus MV, Jacobson C, Gibson CJ, Ebert BL.
Blood Advances. 2021. Aug 10;5(15):2982-2986
*Authors Contributed Equally to This Work

(4) Fitness Landscape of Clonal Hematopoiesis Under Selective Pressure of Immune Checkpoint Blockade (Pubmed)
Miller PG*, Gibson CJ*, Mehta A, Sperling AS, Frederick DT, Manos MP, Miao B, Hacohen N, Hodi FS, Bolan GM, Ebert BL.
Journal of Clinical Oncology Precision Oncology. 2020 Sep 9;4:PO.20.00186.
*Authors Contributed Equally to This Work