Summary Myelodysplastic Syndromes (MDS) arise from a defective hematopoietic stem/progenitor cell. Consequently, there is an urgent need to develop targeted therapies capable of eliminating the MDS-initiating clones. We identified that IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in MDS. MDS clones treated with a small-molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF- κB inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is detrimental to MDS cells while sparing normal CD34+ cells. Based on an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that co-treatment more effectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDS.

IntroductionMyelodysplastic syndrome (MDS) is a hematologic malignancy defined by blood cytopenias due to ineffective hematopoiesis, a predisposition to acute myeloid leukemia (AML), and genomic instability. 1,2 Molecular-targeted therapies do not exist for MDS and the mechanisms of current therapies are largely unknown. More recently, bortezomib (Velcade), which is widely used for the treatment of multiple myeloma (MM) and lymphomas, is being evaluated as a single agent or in combination with chemotherapy in certain MDS and AML patients. [3][4][5] Bortezomib is a selective and reversible inhibitor of the 26S proteasome, and mechanistic studies have revealed that inhibition of the proteasome complex leads to accumulation of lysine (K)-48 ubiquitin-linked proteins and consequently to cytotoxic effects in malignant cells. 6 Proapoptotic and cell-cycle inhibitor proteins are stabilized after proteasome inhibition and thought to contribute to the anticancer effect by inducing apoptosis and inhibiting the cell cycle, respectively. 6 Nevertheless, the molecular and cellular mechanisms of bortezomib-induced cytotoxicity remain unknown, particularly in MDS/AML. Whereas the role of bortezomib in regulating cell-cycle entry and survival have been characterized partially in MDS/AML, 7-9 recent evidence has pointed to a more general cellular effect: bortezomib treatment results in the accumulation of nondegraded proteins, leading to endoplasmic reticulum stress and autophagy in cancer. [10][11][12] Under normal cellular stresses, autophagy, a catabolic pathway, degrades long-lived proteins and defective and superfluous organelles. 13 However, under conditions of extreme cellular stress, autophagy is used by the cell to undergo death. 14 Human miR-146a, a candidate gene in del(5q) MDS/AML, is reduced significantly in del(5q) and normal karyotype MDS/AML patients. [15][16][17] TRAF6 is a key target of miR-146a 15,18,19 and, as expected, miR-146a-knockout mice have a dramatic increase in TRAF6 protein within the hematopoietic compartment. 20,21 Retroviral overexpression of TRAF6 in mouse hematopoietic stem/ progenitor cells results in MDS-like hematopoietic defects and progression to AML. 15 Bortezomib has been shown previously to be effective for an MDS patient with del(5q) and was also reported to reduce directly TRAF6 mRNA and protein in osteoclast precursors from MM patients. 22,23 Because TRAF6 is implicated in MDS/AML and bortezomib has been shown to be effective in del(5q) MDS and to inhibit TRAF6 in MM, we hypothesized that one mechanism of bortezomib action is through inhibition of TRAF6. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org FromIn the present study, we identified TRAF6 as a relevant target of bortezomib-induced...

BackgroundTherapy-related myeloid neoplasms (t-MN), including myelodysplastic syndromes and acute myeloid leukemia (t-MDS and t-AML) are associated to clinical and biologic unfavorable prognostic features, including high levels of DNA methylation.MethodsWe retrospectively evaluated 50 t-MN patients (34 MDS and 16 AML) selected among all patients receiving azacitidine (AZA) at 10 Italian Hematology Centers. Patients had developed a t-MN at a median of 6.5 years (range 1.7- 29) after treatment of the primary tumor (hematological neoplasm, 27 patients; solid tumor, 23 patients).ResultsThe overall response rate was 42% (complete remission: 10 patients, partial remission: 2 and hematological improvement: 8 patients) and was obtained after a median of 3 cycles (range 1–6). Median overall survival (OS) was 21 months (range 1–53.6+) from AZA start. OS was significantly better in patients with less than 20% blasts, in normal karyotype t-AML and when AZA was used as front-line treatment. This was confirmed by the multivariate analysis.ConclusionsThis study reports efficacy of AZA in the largest series of therapy-related MN patients treated with 5-AZA. Our data show that blasts and karyotype maintain their important prognostic role in t-MN also in the azacitidine era.

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Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1β is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56 bright (associated with cytokine relase) were significantly reduced giving rise to NK CD56 dim . Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.