NEW YORK (GenomeWeb) – A new genomic study supports the notion that distinct treatment strategies may be needed to deal with forms of acute myeloid leukemia that develop from chronic blood conditions known as myeloproliferative neoplasms (MPNs).
As they reported in the early, online edition of the Proceedings of the National Academy of Sciences, researchers from Memorial Sloan-Kettering Cancer Center and elsewhere did targeted gene panel sequencing on AML samples from almost three-dozen individuals who developed the disease after living with MPNs. For 13 of the individuals, they also had access to samples collected during the chronic MPN stage, prior to the transformation to full-blown AML.
The team found that the transition to secondary AML often involved a mutation in the JAK2 gene that's been linked to MPNs in the past, as well as TP53 gene mutations that were more frequent than those detected in the chronic MPN phase. Post-MPN AML appeared prone to alterations in genes such as IDH2, ASXL1, and CALR, but was less likely to carry some of the characteristic mutations reported in de novo AML such as changes to the FLT3, CEBPA, and NPM1 genes.
Though the disease often doesn't respond to the sort of induction chemotherapy used to treat other types of AML, follow-up studies of post-MPN AML cell lines and mouse models of the disease hint it may be vulnerable to compounds that target JAK1/2, inhibit the heat shock protein, or dial down methylation in the post-MPN AML genome.
"These data provide genetic evidence that post-MPN AML is a distinct disease from classical AML with a unique mutational spectrum and molecular pathogenesis, and that lack of response to AML chemotherapy regimens reflects the divergent biology of post-MPN AML," senior author Ross Levine, an oncology researcher at Memorial Sloan-Kettering, and his colleagues wrote.
In general, MPNs are marked by excess proliferation of various blood elements — from red or white blood cells to platelets. While the chronic condition does not always progress to leukemia, a proportion of cases do eventually undergo this transformation.
For instance, around 1 percent of individuals with MPN that affects platelets develop AML, the researchers explained. The proportion is slightly higher for those with polycythemia vera, a form of MPN that leads to rampant red blood cell formation. And as many as one-fifth of individuals with excess white blood cell proliferation progress from MPN to AML, they noted.
While past studies have started to unravel the genetic routes and other risk factors that can lead to AML from MPN, authors of the current study decided to use sequencing to take a closer look at this leukemic transformation.
Using a gene sequencing panel targeting 374 genes with ties to hematologic malignancies, the researchers sequenced samples from 33 individuals with post-MPN AML. For 13 of the individuals, they were also able to look at matched samples collected during the chronic stage of MPN before AML developed.
Along with mutations in the targeted cancer-related genes, the team tested for rearrangements in hundreds more genes using DNA or RNA sequence data.
In the overall collection of sequences from the post-MPN AML tumors, the researchers saw previously undetected alterations in genes such as CALR, MYC, PTPN11, and SETBP1, along with genes such as ASXL1, IDH2, SRSF2, and TP53 that had already been implicated in the disease.
When they compared tumors with or without a characteristic MPN-related mutation in JAK2, meanwhile, they found that this glitch often co-occurred with samples harboring changes in TP53 and IDH2, whereas tumors with unaltered versions of JAK2 more often contained mutations affecting CALR and SRSF2.
From paired samples collected before and after AML development, the team found that certain mutations tend to remain relatively steady in their representation, while the frequency of others increased dramatically in the samples collected during post-MPN AML.
The latter included the JAK2 and TP53 mutations, which the researchers linked to leukemic transformation through a series of follow-up analyses and experiments in cell lines and mouse models.
On the other hand, the team found that treatments aimed at dialing down the components of the JAK-STAT signaling pathway could curb blood cell proliferation in mice that developed leukemic disease due to experimental changes to their JAK2 and TP53 genes.
Likewise, those mouse models appeared to respond to other proposed treatments for post-MPN AML such as a heat shock protein 90 inhibitor or a hypomethylating compound, consistent with the notion that these animals may help in finding treatment options for this form of AML, which tends to have poor prognostic outcomes.