LAUSR

Emerging evidence has linked cell mechanics to functional behaviors [1]. The biophysical traits of a single cell are inextricably linked to the cytoskeleton. It has become increasingly evident that intrinsic and extrinsic mechanical properties, which describe the resistance to deformation (elasticity) or flow (viscosity) in response to an applied force, regulate cellular activities, such as cell morphology, adhesion, migration, and trafficking. Recent studies have demonstrated that solid tumor cells with higher migratory and invasive potential are softer than cells with lower migration and invasion potential [2–5]. However, how cell intrinsic mechanical properties might affect liquid tumor (leukemia) development and progression remains unclear. Protein tyrosine phosphatase, non-receptor type 21 (Ptpn21), a poorly studied tyrosine phosphatase [6], binds to actin filaments and regulates cytoskeleton-associated cellular processes [7]. We have recently shown that Ptpn21 plays an important role in maintaining cell mechanical properties [8], and that it helps retain hematopoietic stem cells (HSCs) in the bone marrow (BM) niche through a biomechanical mechanism [8]. Knockout of Ptpn21 results in impaired retention of HSCs within BM niches. Ptpn21 knockout stem cells exhibit enhanced mobility and spontaneous egress into the peripheral blood. These phenotypes were attributable to the decrease in cellular mechanical stiffness and the increase in cell deformability [8]. Mechanistically, Ptpn21 functions by dephosphorylating Spetin1 (Tyr) [8], a rarely described component of the cytoskeleton. Importantly, missense mutations and frameshift truncating mutations in PTPN21 have been identified in chronic lymphocytic leukemia (IntOGen—mutational cancer drivers database) and colon cancer [9–11], respectively. However, the pathogenic effects of PTPN21 loss-offunction mutations remain to be determined. Given the decreased cell mechanical tension and increased deformability displayed by Ptpn21 knockout hematopoietic cells [8], we utilized Ptpn21 knockout (Ptpn21) mice as a model to examine the biomechanical regulation of leukemic development and progression. BM lineage negative (Lin) cells isolated from Ptpn21 or Ptpn21 mice (CD45.2) were transduced with acute myeloid leukemia (AML)-associated oncogene MLL-AF9 and transplanted into sublethally irradiated congenic BoyJ mice (CD45.1). Following in vivo expansion (to obtain sufficient MLL-AF9-transduced cells), leukemic cells were harvested and inoculated into BoyJ mice again (Fig. 1a). Surprisingly, although Ptpn21 was reported to play a positive role in cell signaling (c-Src activation) [12, 13], the recipient mice inoculated with MLL-AF9-Ptpn21 leukemic cells developed AML more quickly than the mice receiving MLL-AF9-Ptpn21 control leukemic cells. The survival of MLL-AF9-Ptpn21 cell recipients was shortened (Fig. 1b). Leukemic burden, as determined by white blood cell counts, spleen weights, and leukemic cells (GFP) in the peripheral blood, BM, and spleen, was markedly increased in the transplants inoculated with MLL-AF9-Ptpn21 cells 15 (Fig. 1c–e) and 25 days These authors contributed equally: Linping Hu, Fang Ni