Calreticulin (CALR) mutations have been reported in Janus kinase 2 (JAK2)– and myeloproliferative leukemia (MPL)–negative essential thrombocythemia and primary myelofibrosis. In contrast, no CALR ...mutations have ever been reported in the context of polycythemia vera (PV). Here, we describe 2 JAK2V617F-JAK2exon12–negative PV patients who presented with a CALR mutation in peripheral granulocytes at the time of diagnosis. In both cases, the CALR mutation was a 52-bp deletion. Single burst-forming units–erythroid (BFU-E) from 1 patient were grown in vitro and genotyped: the same CALR del 52-bp mutation was noted in 31 of the 37 colonies examined; 30 of 31 BFU-E were heterozygous for CALR del 52 bp, and 1 of 31 BFU-E was homozygous for CALR del 52 bp. In summary, although unknown mutations leading to PV cannot be ruled out, our results suggest that CALR mutations can be associated with JAK2-negative PV.
•Major CALR-mutated clones may be observed in polycythemia vera negative for JAK2 mutations.
Heat-shock proteins (HSPs) are powerful chaperones that provide support for cellular functions under stress conditions but also for the homeostasis of basic cellular machinery. All cancer cells ...strongly rely on HSPs, as they must continuously adapt to internal but also microenvironmental stresses to survive. In solid tumors, HSPs have been described as helping to correct the folding of misfolded proteins, sustain oncogenic pathways, and prevent apoptosis. Leukemias and lymphomas also overexpress HSPs, which are frequently associated with resistance to therapy. HSPs have therefore been proposed as new therapeutic targets. Given the specific biology of hematological malignancies, it is essential to revise their role in this field, providing a more adaptable and comprehensive picture that would help design future clinical trials. To that end, this review will describe the different pathways and functions regulated by HSP27, HSP70, HSP90, and, not least, HSP110 in leukemias and lymphomas.
We determined the allelic frequency of the JAK2-V617F mutation in DNA and assessed the expression levels of the mutant and wild-type JAK2 mRNA in granulocytes from 60 patients with essential ...thrombocythemia (ET) and 62 patients with polycythemia vera (PV) at the time of diagnosis. Using allele-specific quantitative polymerase chain reaction (qPCR), we detected JAK2-V617F in 75% of ET and 97% of PV at diagnosis. The total JAK2 mRNA levels were elevated in ET, PV, and secondary and idiopathic erythrocytosis, suggesting that hyperactive hematopoiesis alters JAK2 expression. The expression levels of JAK2-V617F mRNA were variable but strongly correlated with the allelic ratio of JAK2-V617F determined in DNA. Thus, differences in JAK2-V617F expression, markedly lower in ET than in PV, reflected different percentages of granulocytes carrying the mutation. Moreover, allelic ratios higher than 50% JAK2-V617F, indicating the presence of granulocytes homozygous for JAK2-V617F, were found in 70% of PV at diagnosis but never in ET.
Key Points PF4iCre;JAK2 V617F/WT mice develop a full MPN that mimics polycythemia vera. The PF4iCre system induces JAK2V617F mutation in a small subset of HSC.
T-cell and B-cell acute lymphoblastic leukemias (T-ALL, B-ALL) are aggressive hematological malignancies characterized by an accumulation of immature T- or B-cells. Although patient outcomes have ...improved, novel targeted therapies are needed to reduce the intensity of chemotherapy and improve the prognosis of high-risk patients. Using cell lines, primary cells and patient-derived xenograft (PDX) models, we demonstrate that ALL cells viability is sensitive to NVP-BEP800, an ATP-competitive inhibitor of Heat shock protein 90 (HSP90). Furthermore, we reveal that lymphocyte-specific SRC family kinases (SFK) are important clients of the HSP90 chaperone in ALL. When PDX mice are treated with NVP-BEP800, we found that there is a decrease in ALL progression. Together, these results demonstrate that the chaperoning of SFK by HSP90 is involved in the growth of ALL. These novel findings provide an alternative approach to target SRC kinases and could be used for the development of new treatment strategies for ALL.
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