Unprecedented Megakaryocytic Blast Phase Transformation in Chronic Myeloid Leukemia After 16 Years of Tyrosine Kinase Inhibitor Therapy.

We report the case of a 51-year-old Japanese man with chronic myeloid leukemia (CML) initially diagnosed in the chronic phase. For 16 years, the patient maintained chronic phase (CP) under treatment with first- and second-generation tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib, and bosutinib, none of which resulted in ABL1 mutations. However, despite long-term disease stability, the patient experienced an abrupt progression to the megakaryocytic blast phase (MBP), a rare and aggressive form of CML. In response to this progression, ponatinib, a third-generation TKI, was introduced as a fourth-line therapy. Remarkably, within 7 months of initiating ponatinib, the patient achieved a deep molecular response (DMR), evidenced by a reduction in BCR::ABL1 transcript levels to undetectable levels (MR5.0). This molecular remission enabled the patient to proceed with an allogeneic bone marrow transplantation from a human leukocyte antigen (HLA) 8/8-allele-matched unrelated donor. Post-transplantation, the patient has maintained DMR for 14 months without recurrence, despite the challenges posed by graft-versus-host disease. This case illustrates the critical role of third-generation TKIs like ponatinib in managing advanced CML phases, especially when previous therapies fail. It also emphasizes the necessity of vigilant long-term monitoring during the chronic phase to detect and address any signs of disease progression promptly.

Scalable production of homogeneous cardiac organoids derived from human pluripotent stem cells.

Three-dimensional (3D) cultures are known to more closely mimic in vivo conditions compared with 2D cultures. Cardiac spheroids (CSs) and organoids (COs) are useful for 3D tissue engineering and are advantageous for their simplicity and mass production for regenerative therapy and drug discovery. Herein, we describe a large-scale method for producing homogeneous human induced pluripotent stem cell (hiPSC)-derived CSs (hiPSC-CSs) and COs without scaffolds using a porous 3D microwell substratum with a suction system. Our method has many advantages, such as increased efficiency and improved functionality, homogeneity, and sphericity of hiPSC-CSs. Moreover, we have developed a substratum on a clinically relevant large scale for regenerative therapy and have succeeded in producing approximately 40,000 hiPSC-CSs with high sphericity at once. Furthermore, we efficiently produced a fused CO model consisting of hiPSC-derived atrial and ventricular cardiomyocytes localized on opposite sides of one organoid. This method will facilitate progress toward hiPSC-based clinical applications.

Heart-derived collagen promotes maturation of engineered heart tissue.

Although the extracellular matrix (ECM) plays essential roles in heart tissue engineering, the optimal ECM components for heart tissue organization have not previously been elucidated. Here, we focused on the main ECM component, fibrillar collagen, and analyzed the effects of collagens on heart tissue engineering, by comparing the use of porcine heart-derived collagen and other organ-derived collagens in generating engineered heart tissue (EHT). We demonstrate that heart-derived collagen induces better contraction and relaxation of human induced pluripotent stem cell-derived EHT (hiPSC-EHT) and that hiPSC-EHT with heart-derived collagen exhibit more mature profiles than those with collagens from other organs. Further, we found that collagen fibril formation and gel stiffness influence the contraction, relaxation, and maturation of hiPSC-EHT, suggesting the importance of collagen types III and type V, which are relatively abundant in the heart. Thus, we demonstrate the effectiveness of organ-specific collagens in tissue engineering and drug discovery.