Deficit of microRNA (miR)-142 Promotes Transformation of Clonal Myeloid Disorder into Acute Myeloid Leukemia (AML)

AML patients (pts) have an estimated cumulative 5-year survival at a disappointing rate of ~30%, underlying the needs for novel, safer and more effective drugs. A poor prognostic group includes pts with antecedent clonal hematopoietic disorders (ACHD) [i.e., myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs), MDS/MPN (i.e., chronic myelomonocytic leukemia (CMML)] that have transformed into secondary (s) AML. These pts have a significantly worse prognosis than those with de novo AML, and therefore are often excluded from promising clinical trials. The mechanisms of AML transformation are multifaceted and, although have already been long studied, they remain to be fully elucidated.

MiRNAs are short non-coding RNA molecules that downregulate target messenger (m)RNAs and in turn, their encoded proteins. MIR142, located at chromosome band 17q22, is initially transcribed into a primary (pri)-miR-142, and eventually matures into two distinct miRNAs, miR-142-3p and miR-142-5p (hereafter collectively referred to as miR-142). MiR-142 reportedly regulates hematopoiesis and is involved in differentiation and activation of T, NK and dendritic cells. Loss of the mir142 gene in the mouse results in decreased hematopoietic output, and reduction of T, B and NK cells. In humans, miR-142 mutations and/or downregulation have been found in AML, lymphomas, and acute lymphoblastic leukemia.

We have recently reported that abrogation of miR-142 expression causes transformation of chronic phase (CP) chronic myelogenous leukemia (CML) into blast crisis (BC) in murine models (Nat Commun 2023; PMID: 37658085). To determine if a deficit of miR-142 also mediates sAML transformation of other MPNs, we crossed the Mir142^−/− mouse with the Flt3-ITD knock-in (Flt3^ITD/ITD) mouse. While Mir142^+/+Flt3^ITD/ITD mice developed only MPN (median survival: not reached after 630 days), with no evidence of AML, the Mir142^−/−Flt3^ITD/ITD mice progressed to AML and lived significantly shorter (median survival: 304 days, p<0.0001). Importantly, bone marrow (BM) Lin-Sca-1+c-Kit+ cells (LSK) from Mir142^−/−Flt3^ITD/ITD mice yielded an aggressive AML phenotype when transplanted in congenic recipients that survived only 30 days, suggesting transformation of MPN clonal hematopoietic stem and progenitors (HSPCs) into LSCs.

MDSs are a group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis and dysplasia, with an intrinsic risk of transforming into AML. To determine if a deficit of miR-142 is also involved in sAML transformation of MDS, we crossed NHD13 transgenic mouse, a murine MDS model that recapitulates the human disease (PMID: 15755899), with the Mir142^−/− mouse. Different from the Mir142^+/+NHD13 mouse that had pancytopenia but no blasts, the Mir142^−/−NHD13 mouse showed rapid progression to AML, with high white blood cell (WBC) counts (>100k/μl), anemia, thrombocytopenia, 30-90% BM leukemic blasts, and splenomegaly as early as 9 weeks from birth, and had a significantly shorter survival (median survival: 117 vs not reached days, p<0.0001). Importantly, these features were recapitulated in congenic recipients of BM LSK from Mir142^+/+NHD13 donors compared with those of BM LSK from Mir142^−/−NHD13 donors (median survival: 33 days vs not reached, p<0.0001).

While these results support a role of miR-142 in sAML transformation, exploring the mechanisms through which miR-142 deficit transforms MPN/MDS HSPCs into aggressive LSCs remain to be fully elucidated. We have reported an intrinsic role of miR-142 deficit in promoting mitochondrial oxidative metabolism that favors LSC expansion. However, miR-142 deficit also associates with T and NK cell loss-of-function. Consistently, we noted reduced cell number and antileukemic activity (i.e., increased spontaneous apoptosis, reduced cell cycling, reduced cytokine projection, and increased PD-1 expression) of the T and NK cells from both Mir142^−/−Flt3^ITD/ITD and Mir142^−/−NHD13 sAML mice compared with the respective Mir142^+/+Flt3^ITD/ITD and Mir142^+/+NHD13 MPD/MDS controls, suggesting that the miR-142 deficit impaired immune antileukemic surveillance during AML transformation.

In summary, we showed a key role of miR-142 deficit in sAML transformation that supports a possible therapeutic intervention with miR-142 mimic compounds. These treatment studies are ongoing and will be presented at the meeting.