Explore the vast range of titles available.

In this report, two patients with essential thrombocythemia and somatic mutations in the gene encoding calreticulin but no mutations in the Janus kinase 2 gene had a response to interferon alfa therapy. To the Editor: Somatic mutations in the gene encoding calreticulin ( CALR ) were recently described in the majority of patients with myeloproliferative neoplasms without mutations in the Janus kinase 2 gene ( JAK2 ). 1 , 2 We and other groups have previously shown that interferon alfa was able to reduce the JAK2 -mutated clone and to induce molecular complete responses in patients with myeloproliferative neoplasms. 3 Because the effect of interferon alfa on mutant clones in myeloproliferative neoplasms with other molecular lesions is still questioned and because calreticulin was involved in resistance to interferon alfa in hepatitis B virus infection, 4 we . . .

JAK (Janus Kinase) inhibitors, such as ruxolitinib, were introduced a decade ago for treatment of myeloproliferative neoplasms (MPN). To evaluate ruxolitinib’s impact on MPN clonal evolution, we interrogate a myelofibrosis patient cohort with longitudinal molecular evaluation and discover that ruxolitinib is associated with clonal outgrowth of RAS pathway mutations. Single-cell DNA sequencing combined with ex vivo treatment of RAS mutated CD34 + primary patient cells, demonstrates that ruxolitinib induces RAS clonal selection both in a JAK/STAT wild-type and hyper-activated context. RAS mutations are associated with decreased transformation-free and overall survival only in patients treated with ruxolitinib. In vitro and in vivo competition assays demonstrate increased cellular fitness of RAS- mutated cells under ruxolitinib or JAK2 knock-down, consistent with an on-target effect. MAPK pathway activation is associated with JAK2 downregulation resulting in enhanced oncogenic potential of RAS mutations. Our results prompt screening for pre-existing RAS mutations in JAK inhibitor treated patients with MPN. The JAK inhibitor ruxolitinib has been used for treatment of myeloproliferative neoplasms (MPN) and its association with clonal evolution requires further investigation. Here the authors report accumulation of RAS pathway mutations in ruxolitinib-treated myelofibrosis patients, stemming from RAS clonal selection induced by JAK2 inhibition.

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA -immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy. Historical acute promyelocytic leukemia patients treated with retinoic acid and chemotherapy sometimes did relapse. Here the authors performed exome sequencing on 64 patient's samples from diagnosis/relapse/remission and show relapse associates either with cooperating oncogenes at diagnosis, or with unexpected persistence of ancestral pre-leukemic clones.

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches.

Classical myeloproliferative neoplasms (MPNs) are characterized by the proliferation of myeloid cells and the risk of transformation into myelofibrosis or acute myeloid leukemia (AML) and TP53 mutations in MPN patients are linked to AML. However, JAK2V617F has been reported to impact the TP53 response to DNA damage, suggesting potential overlapping role of TP53 inactivation in MPN. We established a mouse model showing that JAK2V617F/Vav-Cre/Trp53 −/− mice displayed a similar phenotype to JAK2V617F/Vav-Cre mice, but their proliferation was outcompeted in competitive grafts. RNA-Seq revealed that half of the genes affected by JAK2V617F were affected by p53-inactivation, including the interferon pathway. To validate this finding, mice were repopulated with a mixture of wild-type and JAK2V617F (or JAK2V617F/Vav-Cre/Trp53 −/− ) cells and treated with pegylated interferonα. JAK2V617F-reconstituted mice entered complete hematological remission, while JAK2V617F/Vav-Cre /Trp53 −/− -reconstituted mice did not, confirming that p53 loss induced interferon-α resistance. KEGG and Gene Ontology analyses of common deregulated genes showed that these genes were mainly implicated in cytokine response, proliferation, and leukemia evolution, illustrating that in this mouse model, the development of MPN is not affected by TP53 inactivation. Taken together, our results show that many genetic modifications induced by JAK2V617F are influenced by TP53, the MPN phenotype may not be. Trp53 loss alone is insufficient to induce rapid leukemic transformation in steady-state hematopoiesis in JAK2V617F MPN, and Trp53 loss may contribute to interferon resistance in MPN.

Immune response induced by COVID-19 vaccine booster against delta and omicron variants was assessed in 65 adults (65–84 years old) early aftesr a first booster dose. An increase in SARS-CoV-2 neutralizing antibodies was shown in individuals not previously infected without evidence of an age-related effect, with lower increase in those infected before a single dose of primary vaccination. Of note, humoral response was observed only starting from the 5th day after the boost.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Jaiswal and colleagues (July 13 issue)1 report that the presence of clonal hematopoiesis of indeterminate potential (CHIP) was associated with coronary heart disease. However, the use of the JAK2 V617F mutation as a marker of CHIP may be misleading, particularly when the mutant allele burden is high (up to 52% in this study). Unlike all the other mutations that were evaluated by the authors, JAK2V617F is an initiating mutation that causes deregulated production of red cells and platelets.2 It is a major criterion in the classification of the World Health Organization (WHO) for a diagnosis of myeloproliferative neoplasms, diseases that are often diagnosed after major thrombosis, including myocardial infarctions.3-5

Juvenile myelomonocytic leukemia (JMML) is an aggressive clonal myeloproliferative neoplasm that affects infants and young children. The narrow window of onset suggests that age‐related factors are involved in leukemogenesis. To investigate whether ontogeny‐related features are involved in JMML oncogenesis, we compared the gene expression profile of hematopoietic progenitor cells isolated from JMML patients with that of healthy individuals at different stages of ontogeny. This analysis identified two main groups of JMML patients. In the first group, JMML progenitors exhibited a gene expression profile similar to that of embryo‐fetal progenitors. Progenitors showed a strong monocytic identity as evidenced by the overexpression of monocytic/dendritic, inflammasome, and innate immune markers. This resembled the monocyte‐predominant myelopoiesis characteristic of normal fetal hematopoiesis. However, in the second group, despite evidence of developmental dysregulation as indicated by the aberrant signature of the master oncofetal regulator LIN28B, JMML clustered separately from healthy prenatal and postnatal fractions. These findings highlight the intricate relationship between JMML and development, which will help inform future therapeutic approaches for this rare but severe form of leukemia.