Myeloproliferative Neoplasm

Our patient carried two acquired molecular abnormalities involving JAK2 gene (PCM1::JAK2 fusion and JAK2 H531Y) along with a germline mutation (BLM Y736fs*5, variant allele frequency VAF 41.7%), whereas his sister had the canonical JAK2 V617F driver mutation. This particular pedigree could arise the hypothesis of a genetic predisposition to acquire different JAK2 molecular abnormalities as a maladaptive somatic genetic rescue of an underlying germline predisposition, namely the germline BLM Y736fs*5 mutation.

P1/2, N=25, Not yet recruiting, Thomas Jefferson University

Further investigation revealed acute myeloid leukemia (AML) arising from blastic transformation of ET, with probable cutaneous involvement consistent with leukemia cutis. This case highlights the importance of maintaining a high index of suspicion when evaluating new or treatment-refractory skin lesions in patients with myeloproliferative neoplasms (MPNs), as early recognition may allow timely diagnosis of leukemic transformation and prompt initiation of appropriate therapy.

This pilot study demonstrates that imaging flow cytometry-based FISH of circulating CD34/CD45-positive cells enables real-time, blood-based surveillance for cytogenetic evolution in myelofibrosis. The ability to dynamically track clone size and hierarchy highlights its potential as an early predictor of leukemic transformation in myelofibrosis.

There were no significant differences in time to blast transformation or time to next treatment depending on PHF6 gene status. According to the results of most studies published to date (SR), PHF6MUT has a prognostic role in MNs; our results are consistent in terms of clinical outcomes, but these marginal effects should be interpreted with caution in the context of existing prognostic models given the limitations of the small sample size.

P=N/A, N=80, Not yet recruiting, Hannover Medical School

Trials assessing the efficacy of pelabresib, ABBV-744, INCB057643, BMS-986158, and OPN-2853 are detailed herein. Research into novel pan-and selective-BETis both as monotherapy and in combination with JAKis or other mechanism-based therapies are ongoing. Whether BETi therapy in MF will ultimately deliver substantial anti-clonal activity to modify disease biology and meaningfully impact clinical outcomes is yet to be determined.

Our findings demonstrate that HIF-1 activation by the JAK2V617F-PIM1 axis significantly alters HIF-1 transcription function, desensitising HIF-1 activity to cellular oxygen levels, and restricting the HIF-1 regulon to a set of disease-associated target genes within JAK2V617F-MPNs. These findings restore the potential for specific therapeutic targeting of HIF-1 by delineating malignant activation from the physiological hypoxic response.

This patient case highlights the likely benign polymorphic nature of the rare G571S JAK2 mutation that has been previously reported. Moreover, our results stress the importance of appropriate interpretation of rare variants of uncertain significance, namely that clinical decision making should be supported by adjunct genetic testing and with appropriate reference to each patient's clinical context.

Although chemotherapy can induce remission in some cases, long-term survival remains limited. The enrollment in clinical trials should be encouraged to improve patient prognosis.

An increased prevalence of second primary malignancy is anticipated due to the rising cancer burden and the careful screening of index initial malignancy throughout therapy. Determining the best course of action requires careful staging of the cancer and discussion by a multidisciplinary team.

In a subcutaneous tumor model, in which Ba/F3 cells expressing JAK2V617F and EpoR were transplanted into nude mice, oral administration of FL118 significantly reduced tumor growth and hepatosplenomegaly. Collectively, these findings establish DDX5 as a promising therapeutic target in MPNs and underscore the potential of FL118 as a treatment strategy for JAK2V617F-driven disease.