Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Abstract

Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

Keywords: Epigenetic target; MPN; PTCL; hematopoietic cancer; mutational landscape; therapeutic target.

Figure 1.

Signaling pathways involved in the pathogenesis of MPNs and secondary AML. JAK2 binds to the cytosolic juxta-membrane region of dimeric cytokine receptors such as MPL (TPOR) and EPOR, via the BOX1 and BOX2 receptor motifs (black lines). JAK2 activation (via receptor-ligand binding or gain-of-function mutation such as JAK2 V617F) promotes various downstream signaling pathways, via STAT5, including RAS-MAPK and PI3K-AKT. These pathways facilitate oncogenic gene transcription and promote cancer cell survival, proliferation or migration. The expression of negative regulators such as the SOCS proteins are induced by the JAK-STAT pathway, however they are not sufficient to block hyperactive JAK-STAT signaling and cannot bind JAK2 V617F. The FLT3-ITD mutant growth factor receptor commonly found in AML patients signals independently of ligand-binding, as a result of the internal tandem duplication (ITD) found within the juxta-membrane domain (red box) and point mutations that occur within the kinase domain (most frequently at D835; dark blue box) of the FLT3 receptor. FLT3-ITD hyperactivation promotes RAS-MAPK, PI3K-AKT as well as STAT5 signaling. A number of important somatic mutations have been reported in various oncogenes and tumor suppressor proteins within these pathways (yellow stars), where such mutations are known to contribute to disease initiation and progression. For further details on these mutations, see Table 1. Mutated calreticulin (CALR), frequently found in MPN patients, interacts with the extracellular portion of the MPL receptor at the Endoplasmic Reticulum-Golgi apparatus and also at the cell surface, promoting direct dimerization, activation of JAK2 and downstream signaling, independently of TPO binding (which is required for normal MPL signaling, indicated by a dashed arrow). Loss-of-function mutations in the critical tumor suppressor protein TP53 are also reported generally in MPN patients that progress to secondary AML. Furthermore, various epigenetic-modifier proteins are found to be mutated in MPN patients, including isocitrate dehydrogenase 1 (IDH1), methylcytosine dioxygenase TET2, DNA methyltransferase 3A (DNMT3A), Polycomb group protein ASXL1 and the histone methyltransferase protein of polycomb repressive complex 2 (PRC2) EZH2. Promising therapeutic agents to target these key proteins/pathways in MPN/AML have been developed and are summarized here (black boxes). TPO, thrombopoietin; EPO, erythropoietin; GTP, guanosine triphosphate; TF, transcription factor.

Figure 2.

Signaling pathways involved in the pathogenesis of PTCL. JAK tyrosine kinases bind to the cytosolic juxta-membrane region of dimeric T-cell cytokine receptors such as IL-7Rα, IL-2Rβ, TSLPR and the common gamma chain (γ_c). Conserved juxta-membrane BOX1 and BOX2 cytokine receptor motifs known to bind JAKs are indicated with black lines. Cytokine receptor-ligand binding promotes STAT3/5 tyrosine phosphorylation to facilitate gene transcription to promote cancer cell survival, proliferation or migration. A number of important somatic mutations have been reported in various oncogenes and tumor suppressor proteins within these pathways (yellow stars), where such mutations are known to contribute to disease initiation and progression. For further details on these mutations, see Table 2. GTPase signaling through RAS-RAF (not shown) or mutated RhoA-ROCK pathways are frequently activated in PTCL. T-cell receptor (TCR) activation, involving phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs; orange boxes), triggers various downstream pathways including PI3K-AKT and NF-κB signaling. Furthermore, overexpression of the AKT-activating protein TCL1A, resulting from rearrangements between a TCL1 family gene and TCR loci rendering it under the control of TCR expression-regulating elements, can contribute to aberrant survival signaling and enhanced TCR activation. Loss-of-function mutations in the critical tumor suppressor proteins TP53 and ATM are reported in PTCL. Moreover, various epigenetic-modifier proteins are found to be mutated in PTCL patients, including isocitrate dehydrogenase 2 (IDH2), methylcytosine dioxygenase TET2, DNA methyltransferase 3A (DNMT3A), BCL-6 corepressor (BCOR) and the histone methyltransferase protein of polycomb repressive complex 2 (PRC2) EZH2. Promising therapeutic agents to target these key proteins/pathways in PTCL have been developed and are summarized here (black boxes). IL, interleukin; TSLP, thymic stromal lymphopoietin; CBM, CARMA3-BCL10-MALT1; GEF, guanine nucleotide exchange factor; GTP, guanosine triphosphate; GDP, guanosine diphosphate; TF, transcription factor.