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Review
. 2020 Dec 29;5(1):e516.
doi: 10.1097/HS9.0000000000000516. eCollection 2021 Jan.

Challenges and Perspectives for Therapeutic Targeting of Myeloproliferative Neoplasms

Sime Brkic  1 , Sara C Meyer  1   2
Affiliations
Review

Challenges and Perspectives for Therapeutic Targeting of Myeloproliferative Neoplasms

Sime Brkic et al. Hemasphere. .

Abstract

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders with dysregulated myeloid blood cell production and propensity for transformation to acute myeloid leukemia, thrombosis, and bleeding. Acquired mutations in JAK2, MPL, and CALR converge on hyperactivation of Janus kinase 2 (JAK2) signaling as a central feature of MPN. Accordingly, JAK2 inhibitors have held promise for therapeutic targeting. After the JAK1/2 inhibitor ruxolitinib, similar JAK2 inhibitors as fedratinib are entering clinical use. While patients benefit with reduced splenomegaly and symptoms, disease-modifying effects on MPN clone size and clonal evolution are modest. Importantly, response to ruxolitinib may be lost upon treatment suggesting the MPN clone acquires resistance. Resistance mutations, as seen with other tyrosine kinase inhibitors, have not been described in MPN patients suggesting that functional processes reactivate JAK2 signaling. Compensatory signaling, which bypasses JAK2 inhibition, and other processes contribute to intrinsic resistance of MPN cells restricting efficacy of JAK2 inhibition overall. Combinations of JAK2 inhibition with pegylated interferon-α, a well-established therapy of MPN, B-cell lymphoma 2 inhibition, and others are in clinical development with the potential to enhance therapeutic efficacy. Novel single-agent approaches targeting other molecules than JAK2 are being investigated clinically. Special focus should be placed on myelofibrosis patients with anemia and thrombocytopenia, a delicate patient population at high need for options. The extending range of new treatment approaches will increase the therapeutic options for MPN patients. This calls for concomitant improvement of our insight into MPN biology to inform tailored therapeutic strategies for individual MPN patients.

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Figures

Figure 1.
Figure 1.
Mechanisms of resistance to Janus kinase 2 (JAK2) inhibitors. Resistance to JAK2 inhibition may develop via acquisition of JAK2 resistance mutations (genetic resistance) or via the formation of JAK family heterodimers of JAK2 with JAK1 or tyrosine kinase 2 (TYK2), which functionally sustain downstream signaling (adaptive resistance). Intrinsic resistance to JAK2 inhibition may relate to compensatory activation of downstream signaling pathways as, for example, the mitogen-activated protein kinase (MAPK) pathway due to bypass activation via receptor tyrosine kinases as, for example, platelet-derived growth factor receptor. The figure was created with BioRender. PI3K = phosphoinositide 3-kinase; STAT = signal transducer and activator of transcription.
Figure 2.
Figure 2.
Potential therapeutic targets in myeloproliferative neoplasms. Targeted molecules highlighted in red are inhibited, targeted molecules highlighted in green are activated. Ac = acetyl group; BAD = BCL2-associated agonist of cell death; BAK = BCL2 antagonist/killer; BAX = BCL2 associated X; BCL-2 = B-cell lymphoma 2; BCL-xL = B-cell lymphoma-extra large; BIM = BCL2-interacting mediator of cell death; BRD4 = bromodomain-containing protein 4; CDK4/6 = cyclin-dependent kinase 4/6; cIAP = cellular inhibitor of apoptosis; DNMT3A = DNA methytransferase 3A; ERK1/2 = extracellular signal-regulated kinase 1/2; FLT3 = FMS-like tyrosine kinase 3; HDAC = histone deacetylase; HSCs = hematopoietic stem cells; HSP90 = heat shock protein 90; IFN-α = interferon-alpha; ILR = interleukin receptor; JAK = Janus kinase; LSD1 = lysine-specific histone demethylase 1; MDM2 = mouse double minute 2 homolog; Me = methyl group; MEK1/2 = MAPK/ERK kinase 1/2; MPNs = myeloproliferative neoplasms; mTOR = mammalian target of rapamaycin; NFκB = nuclear factor kappa-light-chain-enhancer of activated B cells; PD-1/PD-L1 = programmed cell death protein 1/programmed death ligand-1; PI3K = phosphoinositide 3-kinase; PIM = proviral integration site for Moloney murine leukemia virus; RAF = rapidly accelerated fibrosarcoma; RAS = rat sarcoma viral oncogene homolog; SMAC = second mitochondria-derived activator; SMADs = SMA- and MAD-related proteins; SOCS1 = suppressor of cytokine signaling 1; STAT = signal transducer and activator of transcription; TGF-β = transforming growth factor beta; TNF-α = tumor necrosis factor alpha; TYK2 = tyrosine kinase 2; XIAP = X-linked inhibitor of apoptosis.
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