Cdk6 provides JAK2^V617Fmutant progenitors with a gain of fitness to maintain disease. Mice were euthanized when terminally ill. (A) Kaplan-Meier plot depicting disease onset of immune-compromised NSG recipients injected with 1 × 10⁶ total BM cells of indicated genotype. Mean survival, 180 days (VavCre; JAK2^V617F; Cdk6^+/+, n = 13); mean survival, 267.5 days (VavCre; JAK2^V617F; Cdk6^−/−, n = 8). Recipients transplanted with WT Jak2 BM with or without Cdk6 (VavCre; Jak2^+/+; Cdk6^+/+ and VavCre; Jak2^+/+; Cdk6^−/−) did not disease. Log-rank test was used for statistical comparison. n = 4 per genotype; **P < .01; ***P < .001; ****P < .0001. (B) Hematoxylin-eosin staining of BM (scale bars, 100 μm; higher magnifications, 50 μm) and spleen (scale bars, 200 μm; higher magnifications, 50 μm). (C-D) Fold change of frequencies of HSCs (C) and myeloid progenitors (D) in BM and spleen samples of recipients transplanted with VavCre; JAK2^V617F; Cdk6^−/− BM cells (VavCre; JAK2^V617F; Cdk6^+/+ controls set to 1; ***P < .001). (E) Homing in % of Ly5.2⁺ LSKs in 2.5 × 10⁶ BM cells of Ly5.1⁺ recipient mice.