Case Report: Priapism as The Clinical Presenting Feature of Chronic Myeloid Leukemia: Case Report and 20-Year Literature Review

Priapism in chronic myeloid leukemia (CML) appears to be an infrequent manifestation as well as a crucial emergency. Here, we report an 18-year-old male presenting with a persistent erection of the penis for 20 days. We evaluated and compared the reported cases within 20 years discussing the management of priapism in CML. Cytoreductive therapy followed by leukapheresis, the administration of tyrosine kinase inhibitor, and intra-cavernosal blood aspiration may resolve the symptoms of priapism. Early intervention for cytoreduction and aspiration are the pivotal keys to successfully impeding the complications.

Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Therefore, eradicating quiescent CML LSCs is a major goal in CML therapy. Here, using a G0 marker (G0M), we narrow down CML LSCs as G0M- and CD27- double positive cells among the conventional CML LSCs. Whole transcriptome analysis reveals NF-κB activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-κB signals by inhibitors of interleukin-1 receptor-associated kinase 1/4 (IRAK1/4 inhibitors) together with imatinib eliminates mouse and human CML LSCs. Intriguingly, IRAK1/4 inhibitors attenuate PD-L1 expression on CML LSCs, and blocking PD-L1 together with imatinib also effectively eliminates CML LSCs in the presence of T cell immunity. Thus, IRAK1/4 inhibitors can eliminate CML LSCs through inhibiting NF-κB activity and reducing PD-L1 expression. Collectively, the combination of TKIs and IRAK1/4 inhibitors is an attractive strategy to achieve a radical cure of CML.

Novel Mechanism by a Bis-Pyridinium Fullerene Derivative to Induce Apoptosis by Enhancing the MEK-ERK Pathway in a Reactive Oxygen Species-Independent Manner in BCR-ABL-Positive Chronic Myeloid Leukemia-Derived K562 Cells

In the treatment of breakpoint cluster region-Abelson (BCR-ABL)-positive chronic myeloid leukemia (CML) using BCR-ABL inhibitors, the appearance of a gatekeeper mutation (T315I) in BCR-ABL is a serious issue. Therefore, the development of novel drugs that overcome acquired resistance to BCR-ABL inhibitors by CML cells is required. We previously demonstrated that a bis-pyridinium fullerene derivative (BPF) induced apoptosis in human chronic myeloid leukemia (CML)-derived K562 cells partially through the generation of reactive oxygen species (ROS). We herein show that BPF enhanced the activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase (MEK-ERK) pathway in a ROS-independent manner. BPF-induced apoptosis was attenuated by trametinib, suggesting the functional involvement of the MEK-ERK pathway in apoptosis in K562 cells. In addition, the constitutive activation of the MEK-ERK pathway by the enforced expression of the BRAFV600E mutant significantly increased the sensitivity of K562 cells to BPF. These results confirmed for the first time that BPF induces apoptosis in K562 cells through dual pathways—ROS production and the activation of the MEK-ERK pathway. Furthermore, BPF induced cell death in transformed Ba/F3 cells expressing not only BCR-ABL but also T315I mutant through the activation of the MEK-ERK pathway. These results indicate that BPF is as an effective CML drug that overcomes resistance to BCR-ABL inhibitors.

The Downregulation of Both Giant HERCs, HERC1 and HERC2, Is an Unambiguous Feature of Chronic Myeloid Leukemia, and HERC1 Levels Are Associated with Leukemic Cell Differentiation

Large HERC E3 ubiquitin ligase family members, HERC1 and HERC2, are staggeringly complex proteins that can intervene in a wide range of biological processes, such as cell proliferation, DNA repair, neurodevelopment, and inflammation. Therefore, mutations or dysregulation of large HERCs is associated with neurological disorders, DNA repair defects, and cancer. Though their role in solid tumors started to be investigated some years ago, our knowledge about HERCs in non-solid neoplasm is greatly lagging behind. Chronic Myeloid Leukemia (CML) is a model onco-hematological disorder because of its unique and unambiguous relation between genotype and phenotype due to a single genetic alteration. In the present study, we ascertained that the presence of the BCR-ABL fusion gene was inversely associated with the expression of the HERC1 and HERC2 genes. Upon the achievement of remission, both HERC1 and HERC2 mRNAs raised again to levels comparable to those of the healthy donors. Additionally, our survey unveiled that their gene expression is sensitive to different Tyrosine Kinases Inhibitors (TKIs) in a time-dependent fashion. Interestingly, for the first time, we also observed a differential HERC1 expression when the leukemic cell lines were induced to differentiate towards different lineages revealing that HERC1 protein expression is associated with the differentiation process in a lineage-specific manner. Taken together, our findings suggest that HERC1 might act as a novel potential player in blood cell differentiation. Overall, we believe that our results are beneficial to initiate exploring the role/s of large HERCs in non-solid neoplasms.

Comparative Gene Expression Analysis Reveals Similarities and Differences of Chronic Myeloid Leukemia Phases

Chronic myeloid leukemia (CML) is a slowly progressing blood cancer that primarily affects elderly people. Without successful treatment, CML progressively develops from the chronic phase through the accelerated phase to the blast crisis, and ultimately to death. Nowadays, the availability of targeted tyrosine kinase inhibitor (TKI) therapies has led to long-term disease control for the vast majority of patients. Nevertheless, there are still patients that do not respond well enough to TKI therapies and available targeted therapies are also less efficient for patients in accelerated phase or blast crises. Thus, a more detailed characterization of molecular alterations that distinguish the different CML phases is still very important. We performed an in-depth bioinformatics analysis of publicly available gene expression profiles of the three CML phases. Pairwise comparisons revealed many differentially expressed genes that formed a characteristic gene expression signature, which clearly distinguished the three CML phases. Signaling pathway expression patterns were very similar between the three phases but differed strongly in the number of affected genes, which increased with the phase. Still, significant alterations of MAPK, VEGF, PI3K-Akt, adherens junction and cytokine receptor interaction signaling distinguished specific phases. Our study also suggests that one can consider the phase-wise CML development as a three rather than a two-step process. This is in accordance with the phase-specific expression behavior of 24 potential major regulators that we predicted by a network-based approach. Several of these genes are known to be involved in the accumulation of additional mutations, alterations of immune responses, deregulation of signaling pathways or may have an impact on treatment response and survival. Importantly, some of these genes have already been reported in relation to CML (e.g., AURKB, AZU1, HLA-B, HLA-DMB, PF4) and others have been found to play important roles in different leukemias (e.g., CDCA3, RPL18A, PRG3, TLX3). In addition, increased expression of BCL2 in the accelerated and blast phase indicates that venetoclax could be a potential treatment option. Moreover, a characteristic signaling pathway signature with increased expression of cytokine and ECM receptor interaction pathway genes distinguished imatinib-resistant patients from each individual CML phase. Overall, our comparative analysis contributes to an in-depth molecular characterization of similarities and differences of the CML phases and provides hints for the identification of patients that may not profit from an imatinib therapy, which could support the development of additional treatment strategies.