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Single cell approaches identify the molecular network driving malignant hematopoietic stem cell self-renewal

Mairi S. Shepherd, Juan Li, Nicola K. Wilson, Caroline A. Oedekoven, Jiangbing Li, Miriam Belmonte, Juergen Fink, Janine C.M. Prick, Dean C. Pask, Tina L. Hamilton, Dirk Löffler, Anjana Rao, Timm Schroeder, Berthold Göttgens, Anthony R. Green and David G. Kent

Key points

  • Single cell approaches identify regulators of malignant HSC self-renewal.

  • Identification of novel roles for Bmi1, Pbx1 and Meis1 in myeloproliferative neoplasms.

Abstract

Recent advances in single cell technologies have permitted the investigation of heterogeneous cell populations at previously unattainable resolution. Here we apply such approaches to resolve the molecular mechanisms driving disease in mouse hematopoietic stem cells (HSCs), using JAK2V617F mutant myeloproliferative neoplasms (MPNs) as a model. Single cell gene expression and functional assays identified a subset of JAK2V617F mutant HSCs that display defective self-renewal. This defect is rescued at the single HSC level by crossing JAK2V617F mice with mice lacking TET2, the most commonly co-mutated gene in MPN patients. Single cell gene expression profiling of JAK2V617F-mutant HSCs revealed a loss of specific regulator genes, some of which were restored to normal levels in single TET2/JAK2 mutant HSCs. Of these, Bmi1 and, to a lesser extent, Pbx1 and Meis1, overexpression in JAK2-mutant HSCs could drive a disease phenotype and retain durable stem cell self-renewal in functional assays. Together, these single cell approaches refine the molecules involved in clonal expansion of MPNs and have broad implications for deconstructing the molecular network of normal and malignant stem cells.

  • Submitted December 11, 2017.
  • Accepted July 3, 2018.